Publications by authors named "Mahmoud Soliman"

300 Publications

Piece of the puzzle: Remdesivir disassembles the multimeric SARS-CoV-2 RNA-dependent RNA polymerase complex.

Cell Biochem Biophys 2021 Apr 1. Epub 2021 Apr 1.

Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.

The recently emerged SARS-like coronavirus (SARS-CoV-2) has continued to spread rapidly among humans with alarming upsurges in global mortality rates. A major key to tackling this virus is to disrupt its RNA replication process as previously reported for Remdesivir (Rem-P). In this study, we theorize, using computational simulations, novel mechanisms that may underlie the binding of Rem-P to SARS-CoV-2 RdRp-NSPs complex; a multimeric assembly that drives viral RNA replication in human hosts. Findings revealed that while ATP-binding stabilized the replicative tripartite, Rem-P disintegrated the RdRp-NSP complex, starting with the detachment of the NSP7-NSP8 heterodimer followed by minimal displacement of the second NSP8 subunit (NSP8). More so, Rem-P interacted with a relatively higher affinity (ΔG) while inducing high perturbations across the RdRp-NSP domains. D452, T556, V557, S682, and D760 were identified for their crucial roles in stacking the cyano-adenosine and 3,4-dihydroxyoxolan rings of Rem-P while its flexible P tail extended towards the palm domain blocking D618 and K798; a residue-pair identified for essential roles in RNA replication. However, ATP folded away from D618 indicative of a more coordinated binding favorable for nucleotide polymerization. We believe findings from this study will significantly contribute to the structure-based design of novel disruptors of the SARS-CoV-2 RNA replicative machinery.
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http://dx.doi.org/10.1007/s12013-021-00977-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014903PMC
April 2021

Distinguishing the optimal binding mechanism through reversible and irreversible inhibition analysis of HSP72 protein in cancer therapy.

Comput Biol Med 2021 Mar 11;132:104301. Epub 2021 Mar 11.

Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa. Electronic address:

Over the past two decades, covalent inhibitors have gained much interest and are living up to their reputation as a powerful tool in drug discovery. Covalent inhibitors possess several significant advantages, including increased biochemical efficiency, prolonged duration and the ability to target shallow, solvent-exposed substrate-binding domains. One of the enzymes that have been both covalently and non-covalently targeted is the heat shock protein 72 (HSP72). This elevated enzyme expression in cancer cells may be responsible for tumorigenesis and tumor progression by providing chemotherapy resistance. A critical gap remains in the molecular understanding of the structural mechanism's covalent and non-covalent binding to HSP72. In this study, we explore the most optimal binding mechanism in the inhibition of the HSP72. Based on the molecular dynamic analyses, it was evident that the non-covalent complex showed more stability than the covalent complex. The covalent ligand, however, was more able to induce and stabilize the sealed conformation of the HSP72-NBD ATP binding domain throughout the. Also, the non-covalent ligand does not induce any significant conformational change as it remained close to the shape of the unbound complex; and the affinity is only dependent on the multiple hydrogen bonds in contrast to the covalent ligand. This is supported by the secondary structure elements and principal component analysis that was more dominant in the covalently inhibited complex. Covalent bond induced the α-helices sealed conformation of the HSP72-NBD; based on our findings, this will prevent other small molecules from interacting at the ATP binding site domain. Moreover, inhibition of the ATP binding domain can directly affect the ATPs protein folding mechanism of the HSP72 enzyme. The essential dynamic analysis presented in this report compliments the binding mechanism of HSP72, establishing covalent inhibition as the preferred method of inhibiting the HSP72 protein. The findings from this study may assist in the design of more target-specific HSP72 covalent inhibitors exploring the surface-exposed lysine residues.
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http://dx.doi.org/10.1016/j.compbiomed.2021.104301DOI Listing
March 2021

Piecing the fragments together: Dynamical insights into the enhancement of BRD4-BD1 (BET protein) druggability in cancer chemotherapy using novel 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one derivatives.

Curr Pharm Biotechnol 2021 Mar 22. Epub 2021 Mar 22.

Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001. South Africa.

Background: Fragment-based drug discovery in recent times has been explored in the design of highly potent therapeutics.

Methods: In this study, we explored the inhibitory dynamics of Compound 38 (Cpd38), a newly synthesized Bromodomain-containing protein 4 bromodomain 1 (BRD4-BD1) protein inhibitor derived from the synthetic coupling of Fragment 47 (Fgt47) into ABBV-075 scaffold. Using dynamic simulation methods, we unraveled the augmentative effects of chemical fragmentation on improved BRD4-BD1 inhibition.

Results: Findings from this study revealed that although Fgt47 exhibited a considerable ΔGbind, its incorporation into the difluoro-phenoxy pyridine scaffold (Cpd38) notably enhanced the binding affinity. Time-based analyses of interaction dynamics further revealed that the bulkiness of Cpd38 favored its interaction at the BRD4-BD1 active site relative to the fragment. Strikingly, when compared to Fgt47, Cpd38 demonstrated high mobility, which could have enabled it to bind optimally and complementarily with key residues of the active site such as Ile146, Asn140, Cys136, Tyr98, Leu94, Val87, Phe83 and Trp81.

Discussion: On the contrary, majority of these interactions were gradually lost in Fgt47 which could further indicate the essence of coupling it with the difluoro-phenoxy pyridine scaffold. Furthermore, Cpd38 had a more altering effect on BRD4-BDI relative to Fgt47 which could also be as a result of its higher inhibitory activity.

Conclusion: Conclusively, the design of highly potent therapeutics could be facilitated by the incorporation of pharmacologically active small molecule fragments into the scaffold of existing drugs.
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http://dx.doi.org/10.2174/1389201022666210322122056DOI Listing
March 2021

In depth characterisation of the biomolecular coronas of polymer coated inorganic nanoparticles with differential centrifugal sedimentation.

Sci Rep 2021 Mar 19;11(1):6443. Epub 2021 Mar 19.

Centre for Bionano Interactions, University College Dublin, Dublin, Ireland.

Advances in nanofabrication methods have enabled the tailoring of new strategies towards the controlled production of nanoparticles with attractive applications in healthcare. In many cases, their characterisation remains a big challenge, particularly for small-sized functional nanoparticles of 5 nm diameter or smaller, where current particle sizing techniques struggle to provide the required sensitivity and accuracy. There is a clear need for the development of new reliable characterisation approaches for the physico-chemical characterisation of nanoparticles with significant accuracy, particularly for the analysis of the particles in the presence of complex biological fluids. Herein, we show that the Differential Centrifugal Sedimentation can be utilised as a high-precision tool for the reliable characterisation of functional nanoparticles of different materials. We report a method to correlate the sedimentation shift with the polymer and biomolecule adsorption on the nanoparticle surface, validating the developed core-shell model. We also highlight its limit when measuring nanoparticles of smaller size and the need to use several complementary methods when characterising nanoparticle corona complexes.
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http://dx.doi.org/10.1038/s41598-021-84029-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979877PMC
March 2021

Porcine Sapovirus-Induced Tight Junction Dissociation via Activation of RhoA/ROCK/MLC Signaling Pathway.

J Virol 2021 Mar 10. Epub 2021 Mar 10.

Laboratory of Veterinary Pathology, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea

Tight junctions (TJs) are a major barrier and also an important portal of entry for different pathogens. Porcine sapovirus (PSaV) induces early disruption of the TJ integrity of polarized LLC-PK cells, allowing it to bind to the buried occludin co-receptors hidden beneath the TJs on the basolateral surface. However, the signaling pathways involved in the PSaV-induced TJ dissociation are not yet known. Here, we found that the RhoA/ROCK/MLC signaling pathway was activated in polarized LLC-PK cells during the early infection of PSaV Cowden strain in the presence of bile acid. Specific inhibitors of RhoA, ROCK, and MLC restored PSaV-induced reduction of transepithelial resistance, increase of paracellular flux, intracellular translocation of occludin, and lateral membrane lipid diffusion. Moreover, each inhibitor significantly reduced PSaV replication, as evidenced by a reduction in viral protein synthesis, genome copy number, and progeny viruses. The PKC/MLCK and RhoA/ROCK/MYPT signaling pathways, known to dissociate TJs, were not activated during early PSaV infection. Among the above signaling pathways, the RhoA/ROCK/MLC signaling pathway was only activated by PSaV in the absence of bile acid, and specific inhibitors of this signaling pathway restored early TJ dissociation. Our findings demonstrate that PSaV binding to cell surface receptors activates the RhoA/ROCK/MLC signaling pathway, which in turn disrupts TJ integrity via the contraction of the actomyosin ring. Our study contributes to understanding how PSaV enters the cells and will aid in developing efficient and affordable therapies against PSaV and other calicivirus infections.Porcine sapovirus (PSaV), one of the most important enteric pathogens, is known to disrupt tight junction (TJ) integrity to expose its buried co-receptor occludin in polarized LLC-PK cells. However, the cellular signaling pathways that facilitate TJ dissociation are not yet completely understood. Here, we demonstrate that early infection of PSaV in polarized LLC-PK cells in either the presence or absence of bile acids activates the RhoA/ROCK/MLC signaling pathway, whose inhibitors reverse the early PSaV infection-induced early dissociation of TJs and reduce PSaV replication. However, early PSaV infection did not activate the PKC/MLCK and RhoA/ROCK/MYPT signaling pathways, which are also known to dissociate TJs. This study provides a better understanding of the mechanism involved in early PSaV infection-induced disruption of TJs, which is important for controlling or preventing PSaV and other calicivirus infections.
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http://dx.doi.org/10.1128/JVI.00051-21DOI Listing
March 2021

Transcription-translation error: investigation of the structural and functional impact of deleterious single nucleotide polymorphisms in gene.

Inform Med Unlocked 2021 24;22. Epub 2020 Dec 24.

Centre for Genomics Research and Innovation, National Biotechnology Agency, Abuja, Nigeria.

Nonsynonymous single nucleotide polymorphisms (nsSNPs) are one of the most common forms of mutations known to disrupt the product of translation thereby altering the protein structure-function relationship. (PTB domain-containing engulfment adaptor protein 1) is an evolutionarily conserved adaptor protein that has been associated with glycated hemoglobin (HbA1c) in Genome-Wide Association Studies (GWAS). In order to understand the role of in the etiology of diabetes, it is important to study some functional nsSNPs present within the protein. We, therefore, used a SNPinformatics approach to retrieve, classify, and determine the stability effect of some nsSNPs. Y27C, G142D, A144T, and Y149C were jointly predicted by the pathogenic-classifying tools to be disease-causing, however, only G142D, A144T, and Y149C had their structural architecture perturbed as predicted by I-MUTANT and MuPro. Interestingly, G142D and Y149C occur at positions 142 and 149 of which coincidentally are found within the binding site of . Protein-Protein interaction analysis also revealed that interacted with 10 proteins such as Cell division cycle 5-like protein (CDC5L), ADP-ribosylation factor 6 (ARF6), Arf-GAP with coiled-coil (ACAP1), and Multiple epidermal growth factor-like domains protein 10 (MEGF10), etc. Taken together, rs1357922096, rs1264999716, and rs128246649 could be used as genetic biomarkers for the diagnosis of diabetes. However, being a computational study, these nsSNPs require experimental validation to explore their metabolic involvement in the pathogenesis of diseases.
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http://dx.doi.org/10.1016/j.imu.2020.100503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928429PMC
December 2020

East to West not North-West: Structure-Based Mechanistic Resolution of 8-Hydroxyl Replacement and Resulting Effects on the Activities of Imidazole-Based Heme Oxygenase-1 Inhibitors.

Protein J 2021 Apr 1;40(2):166-174. Epub 2021 Mar 1.

Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.

Upregulation of Heme Oxygenase-1 (HO-1) has been widely implicated in cancer growth and chemoresistance. This explains the numerous drug discovery efforts aimed at mitigating its pro-carcinogenic roles till date. In a recent study, two selective azole-based HO-1 inhibitors (Cpd1 and Cpd2) were synthesized, which exhibited differential inhibitory potencies of ~200μm. Interestingly, variations in the affinities of these compounds were determined by their positioning across specific regions of the HO-1 binding domain, pin-pointing a pharmacological interrelationship that remains unresolved. Therefore, in this study, using molecular dynamics simulations and binding free energy calculations, we investigate how dynamical orientations of these compounds influence their binding affinities at the active HO-1 domain. Findings revealed favorable binding for the bromobenzene and imidazole substituents of Cpd1 at the western and eastern regions of the HO-1 active domain. The constituent hydroxyl group was coordinated by residues Asp140 and Arg136 over the simulation period. On the contrary, stable binding of the bromobenzene and imidazole substituents were negated by the optimal orientations of the benzyl substituent, which extended into the northeastern region. These were supported by the displacement of Asp140 and Arg136, crucial for hydrogen bond formation in Cpd1. Also, we observed that Cpd2 exhibited high deviations indicative of an unstable binding relative to Cpd1. This further supports the presumption that Cpd2 was systematically oriented away from the active HO-1 region, a phenomenon that was due to the optimal motions of the benzyl group at the northeastern regions. The highlight of our findings is that the benzyl substituent in Cpd2 elicited negative effects on HO-1, vis a vis, instability, displacement of crucial residues, and low binding energy when compared to Cpd1. Findings pave the way for future drug discovery efforts related to HO-1 inhibition in cancer therapy.
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http://dx.doi.org/10.1007/s10930-021-09969-6DOI Listing
April 2021

Effect of a combination of nitazoxanide, ribavirin, and ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-19.

J Med Virol 2021 05 11;93(5):3176-3183. Epub 2021 Mar 11.

Tropical Medicine and Hepatology Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt.

This trial compared the rate and time of viral clearance in subjects receiving a combination of nitazoxanide, ribavirin, and ivermectin plus Zinc versus those receiving supportive treatment. This non-randomized controlled trial included 62 patients on the triple combination treatment versus 51 age- and sex-matched patients on routine supportive treatment. all of them confirmed cases by positive reverse-transcription polymerase chain reaction of a nasopharyngeal swab. Trial results showed that the clearance rates were 0% and 58.1% on the 7th day and 13.7% and 73.1% on the 15th day in the supportive treatment and combined antiviral groups, respectively. The cumulative clearance rates on the 15th day are 13.7% and 88.7% in the supportive treatment and combined antiviral groups, respectively. This trial concluded by stating that the combined use of nitazoxanide, ribavirin, and ivermectin plus zinc supplement effectively cleared the SARS-COV2 from the nasopharynx in a shorter time than symptomatic therapy.
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http://dx.doi.org/10.1002/jmv.26880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014583PMC
May 2021

Probing Protein-Protein Interactions and Druggable Site Identification: Mechanistic Binding Events between Ubiquitin and Zinc Finger with UFM1-Specific Peptidase Domain Protein (ZUFSP).

Comb Chem High Throughput Screen 2021 Feb 3. Epub 2021 Feb 3.

Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, . South Africa.

Background: Deubiquitinating enzymes (DUBs) protein family have been implicated in some deregulated pathways involved in carcinogenesis such as cell cycle, gene expression, and DNA damage response (DDR). Zinc finger with UFM1-specific peptidase domain protein (ZUFSP) is one of the recently discovered members of the DUBs Objectives: To identify and cross validate the ZUFSP binding site using the bioinformatic tools including SiteMap & Metapocket respectively. To understand the molecular basis of complementary ZUFSP-Ub interaction and associated structural events using MD Simulation Methods: In this study, four binding pockets were predicted, characterized, and cross-validated based on physiochemical features such as site score, druggability score, site volume, and site size. Also, Molecular dynamics simulation technique was employed to determine the impact of ubiquitin-binding on ZUFSP Results: Site 1 with a site score 1.065, Size 102, D scores 1.00, and size volume 261 was predicted to be the most druggable site. Structural studies revealed that upon ubiquitin-binding, the motional movement of ZUFSP was reduced when compared to the unbound ZUFSP. Also, the ZUFSP helical arm (ZHA) domain orient in such a way that it moves closer to the Ub, this orientation enables the formation of a UBD which is very peculiar to ZUFSP.

Conclusion: The impact of ubiquitin on ZUFSP movement and the characterization of its predicted druggable site can be targeted in the development of therapeutics.
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http://dx.doi.org/10.2174/1386207324666210203175142DOI Listing
February 2021

Functional Analysis of Single Nucleotide Polymorphism in ZUFSP Protein and Implication in Pathogenesis.

Protein J 2021 Feb 29;40(1):28-40. Epub 2021 Jan 29.

Molecular Bio-Computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.

Researches have revealed that functional non-synonymous Single Nucleotide Polymorphism (nsSNPs) present in the Zinc-finger with UFM1-Specific Peptidase domain protein (ZUFSP) may be involved in genetic instability and carcinogenesis. For the first time, we employed in-silico approach using predictive tools to identify and validate potential nsSNPs that could be pathogenic. Our result revealed that 8 nsSNPs (rs 112738382, rs 140094037, rs 201652589, rs 201847265, rs 202076827, rs 373634906, rs 375114528, rs 772591104) are pathogenic after being subjected to rigorous filtering process. The structural impact of the nsSNPs on ZUFSP structure indicated that the nsSNPs affect the stability of the protein by lowering ZUFSP protein stability. Furthermore, conservation analysis showed that rs 201652589, rs 140094037, rs 201847265, and rs 772591104 were highly conserved. Interestingly, the protein-protein affinity between ZUFSP and Ubiquitin was altered rs 201652589, rs 140094037, rs 201847265, and rs 772591104 had a binding affinity of - 0.46, - 0.83, - 1.62, and - 1.12 kcal/mol respectively. Our study has been able to identify potential nsSNPs that could be used as genetic biomarkers for some diseases arising as a result of aberration in the ZUFSP structure, however, being a predictive study, the identified nsSNPs need to be experimentally investigated.
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http://dx.doi.org/10.1007/s10930-021-09962-zDOI Listing
February 2021

Exploring the effect of ritonavir and TMC-310911 on SARS-CoV-2 and SARS-CoV main proteases: potential from a molecular perspective.

Future Sci OA 2020 Nov 9;7(1):FSO640. Epub 2020 Nov 9.

Molecular Bio-computation & Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, Kwa-Zulu Natal, South Africa.

Aim: As coronavirus (CoV) disease 2019-associated pneumonia spreads globally, there has been an urgent need to combat the spread and develop vaccines.

Materials & Methods: We used an integrated computational algorithm to explore the binding mechanism of TMC-310911/ritonavir (RVT) with SARS-CoV-2 and SARS-CoV main proteases.

Results: RVT and TMC-310911 had favorable interactions with the proteases, and these high interactions are facilitated by some significant residues such as Asn133, Gly195 and Gln192. Our study further implicated two important rings in the structure of RVT as a possible chemical culprit in its therapeutic activity.

Conclusion: Although there are conflicting clinical results on the therapeutic potency of RVT in the treatment of coronavirus disease 2019, our findings provided molecular insight into the binding mechanism of TMC-310911 and RVT with SARS-CoV-2 and SARS-CoV main proteases.
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http://dx.doi.org/10.2144/fsoa-2020-0079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7651988PMC
November 2020

Validation of Three Different Sterilization Methods of Tilapia Skin Dressing: Impact on Microbiological Enumeration and Collagen Content.

Front Vet Sci 2020 23;7:597751. Epub 2020 Dec 23.

Department of Veterinary Pathology and Clinical Pathology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt.

Tilapia fish skin has demonstrated promise as a stable and practical biological dressing to be used in wound and burn management. However, the appropriate sterilization technique of the Tilapia fish skin is crucial before its clinical application. The standard sterilization technique must eliminate harmful pathogens but maintain the structural and biochemical properties that could compromise the dressing function. This study investigated and compared the efficiency of three sterilizing agents; chlorhexidine gluconate 4% (CHG), povidone iodine 10% (PVP-I), and silver nanoparticles (25 μg/mL) (AgNPs), at three different times (5, 10, and 15 min) on Tilapia fish skin based on the microbial count, histological and collagen properties. Among the sterilization procedures, AgNPs showed rapid and complete antimicrobial activity, with a 100% reduction in microbial growth of the fish skin throughout the treated times. Furthermore, AgNPs did not impair the cellular structure or collagen fibers content of the fish skin. However, CHG and PVP-I caused alterations in the collagen content. This study demonstrated that the AgNPs treatment of Tilapia fish skin provided sterile skin while preserving the histological properties and structural integrity. These findings provide an efficient and quick sterilization method suitable for Tilapia fish skin that could be adopted as a biological dressing.
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http://dx.doi.org/10.3389/fvets.2020.597751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785820PMC
December 2020

A probable means to an end: exploring P131 pharmacophoric scaffold to identify potential inhibitors of Cryptosporidium parvum inosine monophosphate dehydrogenase.

J Mol Model 2021 Jan 9;27(2):35. Epub 2021 Jan 9.

Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.

Compound P131 has been established to inhibit Cryptosporidium parvum's inosine monophosphate dehydrogenase (CpIMPDH). Its inhibitory activity supersedes that of paromomycin, which is extensively used in treating cryptosporidiosis. Through the per-residue energy decomposition approach, crucial moieties of P131 were identified and subsequently adopted to create a pharmacophore model for virtual screening in the ZINC database. This search generated eight ADMET-compliant hits that were examined thoroughly to fit into the active site of CpIMPDH via molecular docking. Three compounds ZINC46542062, ZINC58646829, and ZINC89780094, with favorable docking scores of - 8.3 kcal/mol, - 8.2 kcal/mol, and - 7.5 kcal/mol, were selected. The potential inhibitory mechanism of these compounds was probed using molecular dynamics simulation and Molecular Mechanics Generalized Poisson Boltzmann Surface Area (MM/PBSA) analyses. Results revealed that one of the hits (ZINC46542062) exhibited a lower binding free energy of - 39.52 kcal/mol than P131, which had - 34.6 kcal/mol. Conformational perturbation induced by the binding of the identified hits to CpIMPDH was similar to P131, suggesting a similarity in inhibitory mechanisms. Also, in silico investigation of the properties of the hit compounds implied superior physicochemical properties with regards to their synthetic accessibility, lipophilicity, and number of hydrogen bond donors and acceptors in comparison with P131. ZINC46542062 was identified as a promising hit compound with the highest binding affinity to the target protein and favorable physicochemical and pharmacokinetic properties relative to P131. The identified compounds can serve as a basis for conducting further experimental investigations toward the development of anticryptosporidials, which can overcome the challenges of existing therapeutic options. Graphical abstract P131 and the identified compounds docked in the NAD binding site of Cryptosporidium parvum IMPDH.
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http://dx.doi.org/10.1007/s00894-020-04663-3DOI Listing
January 2021

Predicting cesarean delivery for failure to progress as an outcome of labor induction in term singleton pregnancy.

Am J Obstet Gynecol 2021 Jan 4. Epub 2021 Jan 4.

Fetal Medicine Research Institute, King's College Hospital, London, United Kingdom.

Background: Induction of labor is one of the most common interventions in modern obstetrics, and its frequency is expected to continue to increase. There is inconsistency as to how failed induction of labor is defined; however, the majority of studies define success as the achievement of vaginal delivery. Induction of labor in nulliparous women poses an additional challenge with a 15% to 20% incidence of failure, ending in emergency operative deliveries. The Bishop score has been traditionally used before decisions for induction of labor. Nonetheless, it is subjective and prone to marked interobserver variation. Several studies have been conducted to find alternative predictors, yet a reliable, objective method still remains to be introduced and validated. Hence, there is still a need for the development of new predictive tools to facilitate informed decision making, optimization of resources, and minimization of potential risks of failure. Furthermore, a peripartum transperineal ultrasound scan has been proven to provide objective, noninvasive assessment of labor.

Objective: This study aimed to assess the feasibility of developing and validating an objective and reproducible model for the prediction of cesarean delivery for failure to progress as an outcome of labor induction in term singleton pregnancies.

Study Design: This was a prospective observational cohort study conducted in Cairo University Hospitals and University of Bologna Hospitals between November 2018 and November 2019. We recruited 382 primigravidae with singleton term pregnancies in cephalic presentation. All patients had baseline Bishop scoring together with various transabdominal and transperineal ultrasound assessments of the fetus, maternal cervix, and pelvic floor. The managing obstetricians were blinded to the ultrasound scan findings. The method and indication of induction of labor, the total duration of stages of labor, mode of birth, and neonatal outcomes were all recorded. Women who had operative delivery for fetal distress or indications other than failure to progress in labor were excluded from the final analysis, leaving a total of 344 participants who were randomly divided into 243 and 101 pregnancies that constituted the model development and cross-validation groups, respectively.

Results: It was possible to perform transabdominal and transperineal scans and assess all the required parameters on all study participants. Univariate and multivariate analyses were used for selection of potential predictors and model fitting. The independent predictive variables for cesarean delivery included maternal age (odds ratio, 1.12; P=.003), cervical length (odds ratio, 1.08; P=.04), angle of progression at rest (odds ratio, 0.9; P=.001), and occiput posterior position (odds ratio, 5.7; P=.006). We tested the performance of the prediction model on our cross-validation group. The calculated areas under the curve for the ability of the model to predict cesarean delivery were 0.7969 (95% confidence interval, 0.71-0.87) and 0.88 (95% confidence interval, 0.79-0.97) for the developed and validated models, respectively.

Conclusion: Maternal age and sonographic fetal occiput position, angle of progression at rest, and cervical length before labor induction are very good predictors of induction outcome in nulliparous women at term.
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http://dx.doi.org/10.1016/j.ajog.2020.12.1212DOI Listing
January 2021

Exploring the structural basis and atomistic binding mechanistic of the selective antagonist blockade at D dopamine receptor over D dopamine receptor.

J Mol Recognit 2021 May 5;34(5):e2885. Epub 2021 Jan 5.

Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.

More recently, there has been a paradigm shift toward selective drug targeting in the treatment of neurological disorders, including drug addiction, schizophrenia, and Parkinson's disease mediated by the different dopamine receptor subtypes. Antagonists with higher selectivity for D dopamine receptor (D3DR) over D dopamine receptor (D2DR) have been shown to attenuate drug-seeking behavior and associated side effects compared to non-subtype selective antagonists. However, high conservations among constituent residues of both proteins, particularly at the ligand-binding pockets, remain a challenge to therapeutic drug design. Recent studies have reported the discovery of two small-molecules R-VK4-40 and Y-QA31 which substantially inhibited D3DR with >180-fold selectivity over D2DR. Therefore, in this study, we seek to provide molecular and structural insights into these differential binding mechanistic using meta-analytic computational simulation methods. Findings revealed that R-VK4-40 and Y-QA31 adopted shallow binding modes and were more surface-exposed at D3DR while on the contrary, they exhibited deep hydrophobic pocket binding at D2DR. Also, two non-conserved residues; Tyr36 and Ser182 were identified in D3DR, based on their crucial roles and contributions to the selective binding of R-VK4-40 and Y-QA31. Importantly, both antagonists exhibited high affinities in complex with D3DR compared to D2DR, while van der Waals energies contributed majorly to their binding and stability. Structural analyses also revealed the distinct stabilizing effects of both compounds on D3DR secondary architecture relative to D2DR. Therefore, findings herein pinpointed the origin and mechanistic of selectivity of the compounds, which may assist in the rational design of potential small molecules of the D -like dopamine family receptor subtype with improved potency and selectivity.
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http://dx.doi.org/10.1002/jmr.2885DOI Listing
May 2021

Monthly Intravitreal Infliximab in Behçet's Disease Active Posterior Uveitis: A Long-Term Safety Study.

Retina 2020 Dec 28;Publish Ahead of Print. Epub 2020 Dec 28.

Department of Ophthalmology Department of Internal Medicine, Kasr El Aini Hospital, Cairo University, El-Manial, Cairo, Egypt.

Purpose: To study the safety of extended monthly intravitreal infliximab injections in patients with active posterior uveitis in Behcet's disease (APUBD).

Methods: This is a prospective, interventional, noncomparative, open-label, pilot study of 9 monthly intravitreal infliximab injections (1mg/0.05ml) for twenty-two eyes of 16 patients with APUBD. Control of inflammation and visual outcomes were assessed, and ocular complications were monitored during the study period.

Results: Successful treatment was achieved in 7 eyes (35%) and failure was encountered in 13 eyes (65%). Only seven eyes of 6 patients (35%) had completed the study and achieved complete resolution of inflammation with improved BCVA, and no complications. Failure was either due to inability to control the inflammation in 9 eyes (45%) or development of exacerbation of inflammation in 4 eyes (20%). Four eyes developed severe immunological reaction from the drug following first (n=1), second (n=2), and third (n=1) injections and had to discontinue the injections. Kaplan-Meier survival analysis showed that the mean estimated time to failure was 3.3±0.2 months and all failed eyes required revision of their systemic immunotherapy to control the ocular inflammation.

Conclusion: Intravitreal infliximab for APUBD was associated with a high complication rate and failure to control inflammation in the majority of eyes. It should not be considered a substitute to systemic therapy.
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http://dx.doi.org/10.1097/IAE.0000000000003095DOI Listing
December 2020

Update and Potential Opportunities in CBP [Cyclic Adenosine Monophosphate (cAMP) Response Element-Binding Protein (CREB)-Binding Protein] Research Using Computational Techniques.

Protein J 2021 Feb 4;40(1):19-27. Epub 2021 Jan 4.

Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.

CBP [cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB)-binding protein] is one of the most researched proteins for its therapeutic function. Several studies have identified its vast functions and interactions with other transcription factors to initiate cellular signals of survival. In cancer and other diseases such as Alzheimer's, Rubinstein-taybi syndrome, and inflammatory diseases, CBP has been implicated and hence an attractive target in drug design and development. In this review, we explore the various computational techniques that have been used in CBP research, furthermore we identified computational gaps that could be explored to facilitate the development of highly therapeutic CBP inhibitors.
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http://dx.doi.org/10.1007/s10930-020-09951-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868315PMC
February 2021

Natural Products Database Screening for the Discovery of Naturally Occurring SARS-Cov-2 Spike Glycoprotein Blockers.

ChemistrySelect 2020 Nov 16;5(42):13309-13317. Epub 2020 Nov 16.

Department of Pharmaceutical Chemistry Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus Kochi 682 041 India.

SARS-CoV-2 coronavirus has been recognized the causative agent of the recent and ongoing pandemic. Effective and specific antiviral agents or vaccines are still missing, despite a large plethora of compounds have been proposed and tested worldwide. New compounds are requested urgently and virtual screening can offer fast and robust predictions to investigate. Moreover, natural compounds were shown to exert antiviral effects and can be endowed with limited side effects and wide availability. Our approach consisted in the validation of a docking protocol able to refine the most suitable candidates, within the 31000 natural compounds of the natural product activity and species source (NPASS) library, interacting with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein. After the refinement process two natural compounds, castanospermine and karuquinone B, were shown to be the best-in-class derivatives able to target an essential structure of the virus and to act in the early stage of infection.
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http://dx.doi.org/10.1002/slct.202003349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753608PMC
November 2020

Design, synthesis, and evaluation of "dual-site"-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase.

Eur J Med Chem 2021 Feb 10;211:113063. Epub 2020 Dec 10.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address:

Inspired by our previous efforts to improve the drug-resistance profiles of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a novel series of "dual-site" binding diarylpyrimidine (DAPY) derivatives targeting both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP) were designed, synthesized, and evaluated for their anti-HIV potency in TZM-bl and MT-4 cells. Eight compounds exhibited moderate to excellent potencies in inhibiting wild-type (WT) HIV-1 replication with EC values ranging from 2.45 nM to 5.36 nM, and 14c (EC = 2.45 nM) proved to be the most promising inhibitor. Of note, 14c exhibited potent activity against the single mutant strain E138K (EC = 10.6 nM), being comparable with ETR (EC = 9.80 nM) and 3.5-fold more potent than that of compound 7 (EC = 37.3 nM). Moreover, 14c acted as a classical NNRTI with high affinity for WT HIV-1 RT (IC = 0.0589 μM). The detailed structure-activity relationships (SARs) of the representative compounds were also determined, and further supported by molecular dynamics simulation. Overall, we envision that the "dual-site"-binding NNRTIs have significant prospects and pave the way for the next round of rational design of potent anti-HIV-1 agents.
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http://dx.doi.org/10.1016/j.ejmech.2020.113063DOI Listing
February 2021

Elucidating the Disparate Inhibitory Mechanisms of Novel 1-Heteroaryl1,3-Propanediamine Derivatives and Maraviroc towards C-C Chemokine Receptor 5: Insights for Structural Modifications in HIV-1 Drug Discovery.

Med Chem 2020 Dec 8. Epub 2020 Dec 8.

Molecular Bio-computation and Drug Design Laboratory School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001. South Africa.

Introduction: Blocking Human Immunodeficiency Virus type 1 (HIV-1) entry via C-C chemokine receptor 5 (CCR5) inhibition has remained an essential strategy in HIV drug discovery. This underlies the development of CCR5 blockers, such as Maraviroc, which, however, elicits undesirable side effects despite its potency.

Background: Recent lead optimization efforts led to the discovery of novel 1-heteroaryl-1,3-propanediamine derivatives; Compd-21 and -34, which were ~3 times more potent than Maraviroc, with improved pharmacokinetics. However, atomistic molecular interaction mechanism of how slight structural variance between these inhibitors significantly affects their binding profiles have not been elucidated.

Method: This study employed explicit lipid bilayer molecular dynamics (MD) simulations, and advance analyses to explore these inhibitory discrepancies.

Results: Findings revealed that the thiophene moiety substitution common to Compd-21 and -34 enhanced their CCR5- inhibitory activities due to complementary high-affinity interactions with Trp862.60, Tyr1083.32, Tyr2516.51, Glu2837.39. These cumulatively accounted for their ΔGbind which were higher than Maraviroc. Binding dynamics further revealed that the compounds mediated direct competitive inhibition at CCR5 by blocking the gp120 V3 loop. Furthermore, constituent tropane and triazole moieties in the compounds commonly engaged in interactions with Glu2837.39 and Trp862.60, respectively. Structural analyses also revealed that both Compd-21 and -34 elicited distinct internal dynamic effect on CCR5 relative to Maraviroc.

Conclusion: Structural modifications at the thiophene substituent and the addition of new functional groups to the triazole ring may enhance inhibitor competition with gp120 V3-loop. Findings herein highlighted would contribute to future structure-based design of inhibitors of HIV-1 CCR5 with improved potencies.
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http://dx.doi.org/10.2174/1573406417666201208122110DOI Listing
December 2020

Investigating the Mechanistic Inhibitory Discrepancies of Novel Halogen and Alkyl Di-Substituted Oxadiazole-Based Dibenzo-Azepine-Dione Derivatives on Poly (ADP-Ribose) Polymerase-1.

Chem Biodivers 2021 Jan 22;18(1):e2000802. Epub 2020 Dec 22.

Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.

Numerous studies have established the involvement of Poly (ADP-ribose) Polymerase-1 (PARP-1) in cancer presenting it as an important therapeutic target over recent years. Although homology among the PARP protein family makes selective targeting difficult, two compounds [d11 (0.939 μM) and d21 (0.047 μM)] with disparate inhibitory potencies against PARP-1 were recently identified. In this study, free energy calculations and molecular simulations were used to decipher underlying mechanisms of differential PARP-1 inhibition exhibited by the two compounds. The thermodynamics calculation revealed that compound d21 had a relatively higher ΔG than d11. High involvement of van der Waal and electrostatic effects potentiated the affinity of d21 at PARP-1 active site. More so, incorporated methyl moiety in d11 accounted for steric hindrance which, in turn, prevented complementary interactions of key site residues such as TYR889, MET890, TYR896, TYR907. Conformational studies also revealed that d21 is more stabilized for interactions in the active site compared to d11. We believe that findings from this study would provide an important avenue for the development of selective PARP-1 inhibitors.
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http://dx.doi.org/10.1002/cbdv.202000802DOI Listing
January 2021

Exploiting the tolerant region I of the non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket. Part 2: Discovery of diarylpyrimidine derivatives as potent HIV-1 NNRTIs with high Fsp values and favorable drug-like properties.

Eur J Med Chem 2021 Mar 27;213:113051. Epub 2020 Nov 27.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong, Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address:

To yield potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with favorable drug-like properties, a series of novel diarylpyrimidine derivatives targeting the tolerant region I of the NNRTI binding pocket were designed, synthesized and biologically evaluated. The most active inhibitor 10c exhibited outstanding antiviral activity against most of the viral panel, being about 2-fold (wild-type, EC = 0.0021 μM), 1.7-fold (K103N, EC = 0.0019 μM), and slightly more potent (E138K, EC = 0.0075 μM) than the NNRTI drug etravirine (ETR). Additionally, 10c was endowed with relatively low cytotoxicity (CC = 18.52 μM). More importantly, 10c possessed improved drug-like properties compared to those of ETR with an increased Fsp (Fraction of sp carbon atoms) value. Furthermore, the molecular dynamics simulation and molecular docking studies were implemented to reveal the binding mode of 10c in the binding pocket. Taken together, 10c is a promising lead compound that is worth further investigation.
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http://dx.doi.org/10.1016/j.ejmech.2020.113051DOI Listing
March 2021

Population PK-PD-PD Modeling of Recombinant Follicle Stimulating Hormone in In Vitro Fertilization/Intracytoplasmic Sperm Injection: Implications on Dosing and Timing of Gonadotrophin Therapy.

J Clin Pharmacol 2021 May 29;61(5):700-713. Epub 2020 Dec 29.

Department of Obstetrics and Gynecology, Cairo University, Cairo, Egypt.

This study aimed to characterize an interactive and clinically applicable population pharmacokinetic-pharmacodynamic-pharmacodynamic (PK-PD-PD) model describing follicle-stimulating hormone (FSH)-inhibin B-oocyte relationship in women undergoing assisted reproduction with in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). The study was a prospective analysis of 25 healthy women undergoing IVF/ICSI using gonadotropin-releasing hormone (GnRH) antagonist protocol. The developed model used the FSH PK profiles to predict both inhibin B (first PD end point) and oocyte retrieval (second PD end point). The modeling framework involved 2 stages. First, the FSH-inhibin B model was developed by the simultaneous approach and applied to estimate the individual area under the inhibin B-time curve (AUC ) at the end of stimulation cycles that varied in length in each woman. In the second stage, the estimated AUC was introduced as a link covariate to predict oocyte retrieval and response category. The population FSH-inhibin B model was described as 3 submodels; PK (exogenous), endogenous, and inhibin B PD models. Weight was the main determinant of both endogenous and exogenous FSH exposures. GnRH antagonist therapy was a significant time-varying covariate when tested against the endogenous FSH production rate (P < .001). AUC could be predicted with women's age and weight. Log-transformed AUC was a significant covariate when tested against oocyte retrieval (P < .001). Simulations concluded a target AUC of 144-303 ng·h/mL for optimal ovarian response. The GnRH antagonist was better started on day 7 of the cycle. Covariate-based dosing suggests lower recombinant follicle-stimulating hormone requirements in a thin and/or young population. An interactive web application "GonadGuide" was developed to facilitate the application in clinical practice.
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http://dx.doi.org/10.1002/jcph.1792DOI Listing
May 2021

Evaluation of fish skin as a biological dressing for metacarpal wounds in donkeys.

BMC Vet Res 2020 Dec 3;16(1):472. Epub 2020 Dec 3.

Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Assiut University, Assiut, 71526, Egypt.

Background: The use of biological dressings has recently emerged in the management of burns and wounds. The aim of the present study was to evaluate the Nile tilapia skin as a biological dressing for full-thickness cutaneous metacarpal wounds in donkeys. The study was conducted on nine clinically healthy donkeys (n = 9). Here, fish skin dressings were obtained from fresh Nile tilapia (Oreochromis niloticus and sterilized by immersion in silver nanoparticles (AgNPs) solution for 5 min, with no change in collagen content. Bilateral, circular full-thickness excisional skin wounds (2 cm in diameter) were created on the dorsal aspect of the mid-metacarpals of each donkey. Wounds on the right metacarpals (treated wounds, n = 9) were dressed with sterile fish skins, while wounds on the left metacarpals (control wounds, n = 9) were dressed with sterile non-adherent dressing pads without any topical applications. Wound dressings were changed weekly. Wounds were evaluated microbiologically, grossly, and histologically on days 7, 14, and 21 post-wound inductions.

Results: Fish skin-dressed wounds showed a significant (P < 0.0001) reduction in microbial counts (Total viable bacterial count, Staphylococcal count, and Coliform count), a significant (P < 0.0001) decrease in the wound size, and a significant reduction (P < 0.0001) in the epithelial gap compared to the untreated wounds. No frequent dressing changes were needed.

Conclusions: Fish skin dressing accelerated the wound healing process and efficiently inhibited the local microbial activity and exuberant granulation tissue formation suggesting its reliable and promising application for metacarpal wounds of donkeys.
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http://dx.doi.org/10.1186/s12917-020-02693-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713020PMC
December 2020

Therapeutic Path to Double Knockout: Investigating the Selective Dual-Inhibitory Mechanisms of Adenosine Receptors A1 and A2 by a Novel Methoxy-Substituted Benzofuran Derivative in the Treatment of Parkinson's Disease.

Cell Biochem Biophys 2021 Mar 22;79(1):25-36. Epub 2020 Nov 22.

Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.

The dual inhibition of adenosine receptors A1 (A AR) and A2 (A AR) has been considered as an efficient strategy in the treatment of Parkinson's disease (PD). This led to the recent development of a series of methoxy-substituted benzofuran derivatives among which compound 3j exhibited dual-inhibitory potencies in the micromolar range. Therefore, in this study, we seek to resolve the mechanisms by which this novel compound elicits its selective dual targeting against A AR and A AR. Unique to the binding of 3j in both proteins, from our findings, is the ring-ring interaction elicited by Phe275 (→ Phe170) with the benzofuran ring of the compound. As observed, this π-stacking interaction contributes notably to the stability of 3j at the active sites of A and A AR. Besides, conserved active site residues in the proteins such as Ala170 (→ Ala65), Ile173 (→ Ile68), Val191 (→ Val86), Leu192 (→ Leu87), Ala195 (→ Ala90), Met284 (→ Met179), Tyr375 (→ Tyr369), Ile378 (→ Ile372), and His382 (→ His376) were commonly involved with other ring substituents which further complement the dual binding and stability of 3j. This reflects a similar interaction mechanism that involved aromatic (π) interactions. Consequentially, vdW energies contributed immensely to the dual binding of the compound, which culminated in high ΔG that were homogenous in both proteins. Furthermore, 3j commonly disrupted the stable and compact conformation of A and A AR, coupled with their active sites where Cα deviations were relatively high. Ligand mobility analysis also revealed that both compounds exhibited a similar motion pattern at the active site of the proteins relative to their optimal dual binding. We believe that findings from this study with significantly aid the structure-based design of highly selective dual-inhibitors of A and A AR.
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http://dx.doi.org/10.1007/s12013-020-00957-8DOI Listing
March 2021

Formulation of pH-Responsive Quatsomes from Quaternary Bicephalic Surfactants and Cholesterol for Enhanced Delivery of Vancomycin against Methicillin Resistant .

Pharmaceutics 2020 Nov 14;12(11). Epub 2020 Nov 14.

Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban 4000, South Africa.

Globally, human beings continue to be at high risk of infectious diseases caused by methicillin-resistant (MRSA); and current treatments are being depleted due to antimicrobial resistance. Therefore, the synthesis and formulation of novel materials is essential for combating antimicrobial resistance. The study aimed to synthesize a quaternary bicephalic surfactant (StBAclm) and thereof to formulate pH-responsive vancomycin (VCM)-loaded quatsomes to enhance the activity of the antibiotic against MRSA. The surfactant structure was confirmed using H, C nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FT-IR), and high-resolution mass spectrometry (HRMS). The quatsomes were prepared using a sonication/dispersion method and were characterized using various in vitro, in vivo, and in silico techniques. The in vitro cell biocompatibility studies of the surfactant and pH-responsive vancomycin-loaded quatsomes (VCM-StBAclm-Qt) revealed that they are biosafe. The prepared quatsomes had a mean hydrodynamic diameter (MHD), polydispersity index (PDI), and drug encapsulation efficiency (DEE) of 122.9 ± 3.78 nm, 0.169 ± 0.02 mV, and 52.22 ± 8.4%, respectively, with surface charge switching from negative to positive at pH 7.4 and pH 6.0, respectively. High-resolution transmission electron microscopy (HR-TEM) characterization of the quatsomes showed spherical vesicles with MHD similar to the one obtained from the zeta-sizer. The in vitro drug release of VCM from the quatsomes was faster at pH 6.0 compared to pH 7.4. The minimum inhibitory concentration (MIC) of the drug loaded quatsomes against MRSA was 32-fold and 8-fold lower at pH 6.0 and pH 7.4, respectively, compared to bare VCM, demonstrating the pH-responsiveness of the quatsomes and the enhanced activity of VCM at acidic pH. The drug-loaded quatsomes demonstrated higher electrical conductivity and a decrease in protein and deoxyribonucleic acid (DNA) concentrations as compared to the bare drug. This confirmed greater MRSA membrane damage, compared to treatment with bare VCM. The flow cytometry study showed that the drug-loaded quatsomes had a similar bactericidal killing effect on MRSA despite a lower (8-fold) VCM concentration when compared to the bare VCM. Fluorescence microscopy revealed the ability of the drug-loaded quatsomes to eradicate MRSA biofilms. The in vivo studies in a skin infection mice model showed that groups treated with VCM-loaded quatsomes had a 13-fold decrease in MRSA CFUs when compared to the bare VCM treated groups. This study confirmed the potential of pH-responsive VCM-StBAclm quatsomes as an effective delivery system for targeted delivery and for enhancing the activity of antibiotics.
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http://dx.doi.org/10.3390/pharmaceutics12111093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696852PMC
November 2020

Could chroman-4-one derivative be a better inhibitor of PTR1? - Reason for the identified disparity in its inhibitory potency in Trypanosoma brucei and Leishmania major.

Comput Biol Chem 2021 Feb 7;90:107412. Epub 2020 Nov 7.

Molecular Bio-Computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa. Electronic address:

Most notable Kinetoplastids are of the genus Trypanosoma and Leishmania, affecting several millions of humans in Africa and Latin America. Current therapeutic options are limited by several drawbacks, hence the need to develop more efficacious inhibitors. An investigation to decipher the mechanism behind greater inhibitory potency of a chroman-4-one derivative (compound 1) in Trypanosoma brucei pteridine reductase 1 (TbPTR1) and Leishmania major pteridine reductase 1 (LmPTR1) was performed. Estimation of ΔG revealed that compound 1 had a greater binding affinity in TbPTR1 with a ΔG value of -49.0507 Kcal/mol than -29.2292 Kcal/mol in LmPTR1. The ΔGbind in TbPTR1 were predominantly contributed by "strong" electrostatic energy compared to the "weak" van der Waals in LmPTR1. In addition to this, the NADPH cofactor contributed significantly to the total energy of TbPTR1. A characteristic weak aromatic π interaction common in PTR1 was more prominent in TbPTR1 than LmPTR1. The consistent occurrence of high-affinity conventional hydrogen bond interactions as well as a steady interaction of crucial active site residues like Arg14/Arg17, Ser95/Ser111, Phe97/Phe113 in TbPTR1/LmPTR1 with chroman-4-one moiety equally revealed the important role the moiety played in the activity of compound 1. Overall, the structural and conformational analysis of the active site residues in TbPTR1 revealed them to be more rigid than LmPTR1. This could be the mechanism of interaction TbPTR1 employs in exerting a greater potency than LmPTR1. These findings will further give insight that will be assistive in modifying compound 1 for better potency and the design of novel inhibitors of PTR1.
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http://dx.doi.org/10.1016/j.compbiolchem.2020.107412DOI Listing
February 2021

Evaluation of the Cesarean Scar Niche In Women With Secondary Infertility Undergoing ICSI Using 2D Sonohysterography Versus 3D Sonohysterography and Setting a Standard Criteria; Alalfy Simple Rules for Scar Assessment by Ultrasound To Prevent Health Problems for Women.

Int J Womens Health 2020 3;12:965-974. Epub 2020 Nov 3.

Obstetrics and Gynecology Department, Kasr Alainy, Faculty of Medicine, Cairo University, Egypt, Algezeera Hospital, Egypt.

Background: Many expressions were used to define the defect that is seen by ultrasound after cesarean section (CS) namely scar defect, niche, isthmocele, uterine pouch or diverticula.

Objective: To compare the accuracy of 2 dimensional sonohysterography (2D SHG) to 3 dimensional sonohysterography (3D SHG) in evaluating cesarean section uterine scar depth (D), base width (BW), width (W) and residual myometrial thickness (RMT) in women with secondary infertility and establishment of a standard criteria; Alalfy simple rules for scar assessment.

Patients And Methods: This was an observational cross-sectional comparative study that was conducted on women who presented with secondary infertility and were candidates for intracytoplasmic sperm injection (ICSI) and giving a history of a previous cesarean section. Assessment of uterine scar in each woman was performed using 2D transvaginal ultrasound with sonohysterography (SHG) followed by 3D transvaginal with SHG with evaluation of niche depth, width, RMT, niche BW and RMT/depth ratio. The study was conducted at Algezeera hospital, Egypt.

Results: The present study revealed that 3D ultrasound with SHG is superior in evaluation of the RMT and niche width prior to ICSI providing better characterization of the scar niche.

Conclusion: Scar niche should be assessed by a combined integrated 2D SHG and 3D SHG scan with the specific geometrical and anatomical considerations, Alalfy simple rules for scar niche assessment that involvemeasurement of niche depth, (Base width) BW, width, RMT and RMT/depth ratio in sagittal plane, RMT in coronal plane / niche width in coronal plane ratio (ratio less than 1 denotes scar weakness with more liability for dehiscence).

Trial Registration: Clinical Trials.gov Id NCT04076904.
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http://dx.doi.org/10.2147/IJWH.S267691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650036PMC
November 2020

Weak spots inhibition in the antigen 85C target for antitubercular drug design through selective irreversible covalent inhibitor-SER124.

J Biomol Struct Dyn 2020 Nov 6:1-21. Epub 2020 Nov 6.

Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.

() encoded secreted antigen 85 enzymes (Ag85A/Ag85B/Ag85C) play that critical roles in the virulence, survival and drug-resistant TB of the pathogen. Ag85 proteins are potential antitubercular drug targets because they are essential in the catalytic synthesis of trehalose moieties and mycolic acid attachment to the cell wall. Recently, experimental protocols led to the discovery of a selective covalent Ag85 inhibitor, β-isomer monocyclic enolphosphorus Cycliphostin (CyC) compound, which targets the Ag85 serine 124 to exhibit a promising therapeutic activity. For the first time, our study unravelled the structural features among Ag85C homologs and motions and dynamics of Ag85C when the CyC bound covalently and in open model conformations to the protein using bioinformatics tools and integrated Molecular dynamics simulations. Comparative Ag85C sequence analysis revealed conserved regions; 70% active site, 90% Adeniyi loop L1 and 50% loop L2, which acts as a switch between open and closed conformations. The average C-α atoms RMSD (2.05 Å) and RMSF (0.9 Å) revealed instability and high induced flexibility in the CyC covalent-bound compared to the apo and open model systems, which displayed more stability and lower fluctuations. DSSP showed structural transitions of α-helices to bend and loops to 3-helices in the bound systems. SASA of CyC covalent bound showed active site hydrophobic residues exposure to huge solvent. Therefore, these findings present the potential opportunity hotspots in Ag85C protein that would aid the structure-based design of novel chemical entities capable of resulting in potent antitubercular drugs. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1844061DOI Listing
November 2020

Epidemiological and Histopathological Investigation of spp. in Slaughtered Dromedary Camels () in Egypt.

Vet Sci 2020 Oct 27;7(4). Epub 2020 Oct 27.

Department of Biomedical Sciences, University of León (ULE), 24071 León, Spain.

Sarcocystosis is considered one of the major parasitic diseases with a worldwide distribution. It is caused by the obligatory intracellular protozoan parasites of the genus . Besides its public health issues, sarcocystosis results in significant economic losses due to its impact on productivity and milk yield. A wide range of final and intermediate hosts have been identified, including mammals, birds, and reptiles; however, few studies have investigated the contribution of camels to maintaining the epidemiological foci of the disease in countries such as Egypt. The present study was conducted to grossly and histopathologically identify the prevalence rate of spp. in camels ( = 100) from the Aswan Governorate, Egypt. Furthermore, the major risk factors related to the development of sarcocystosis in camels were investigated. Samples from the diaphragm, cardiac muscle, esophagus, and testes of the slaughtered camels were collected. Interestingly, was detected in 75% of the examined camels. Following the studied variable factors, camels aged 5 years or more were found to be at higher risk, with an infection rate of 87.7% (57 of 65) than those younger than 5 years. The infection rate was 81.4% (57 of 70) in males and 60% (18 of 30) in females. The esophagus was the most affected organ (49%), followed by the diaphragm (26%) and cardiac muscle (17%), whereas none of the testes samples were affected. Taken together, the present study demonstrates the high prevalence of in the examined camels and suggests the importance of these animals in preserving the epidemiological foci of sarcocystosis in Egypt. Future research should map the circulating strains in Egypt and aim to raise public health awareness about the importance of sarcocystosis and other related zoonotic diseases.
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http://dx.doi.org/10.3390/vetsci7040162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711966PMC
October 2020