Publications by authors named "Usman Ali Ashfaq"

112 Publications

Computer-Aided Multi-Epitope Vaccine Design against .

Int J Environ Res Public Health 2022 Jun 23;19(13). Epub 2022 Jun 23.

Department of Health and Biological Sciences, Abasyn University, Peshawar 25000, Pakistan.

Antibiotic resistance is a global public health threat and is associated with high mortality due to antibiotics' inability to treat bacterial infections. is an emerging antibiotic-resistant bacterial pathogen from the Enterobacter genus and has the ability to acquire resistance to multiple antibiotic classes. Currently, there is no effective vaccine against Enterobacter species. In this study, a chimeric vaccine is designed comprising different epitopes screened from proteomes using immunoinformatic and bioinformatic approaches. In the first phase, six fully sequenced proteomes were investigated by bacterial pan-genome analysis, which revealed that the pathogen consists of 21,996 core proteins, 3785 non-redundant proteins and 18,211 redundant proteins. The non-redundant proteins were considered for the vaccine target prioritization phase where different vaccine filters were applied. By doing so, two proteins; ferrichrome porin (FhuA) and peptidoglycan-associated lipoprotein (Pal) were shortlisted for epitope prediction. Based on properties of antigenicity, allergenicity, water solubility and DRB*0101 binding ability, three epitopes (GPAPTIAAKR, ATKTDTPIEK and RNNGTTAEI) were used in multi-epitope vaccine designing. The designed vaccine construct was analyzed in a docking study with immune cell receptors, which predicted the vaccine's proper binding with said receptors. Molecular dynamics analysis revealed that the vaccine demonstrated stable binding dynamics, and binding free energy calculations further validated the docking results. In conclusion, these in silico results may help experimentalists in developing a vaccine against in specific and Enterobacter in general.
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http://dx.doi.org/10.3390/ijerph19137723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9265868PMC
June 2022

Structural Elucidation of Rift Valley Fever Virus L Protein towards the Discovery of Its Potential Inhibitors.

Pharmaceuticals (Basel) 2022 May 25;15(6). Epub 2022 May 25.

Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia.

Rift valley fever virus (RVFV) is the causative agent of a viral zoonosis that causes a significant clinical burden in domestic and wild ruminants. Major outbreaks of the virus occur in livestock, and contaminated animal products or arthropod vectors can transmit the virus to humans. The viral RNA-dependent RNA polymerase (RdRp; L protein) of the RVFV is responsible for viral replication and is thus an appealing drug target because no effective and specific vaccine against this virus is available. The current study reported the structural elucidation of the RVFV-L protein by in-depth homology modeling since no crystal structure is available yet. The inhibitory binding modes of known potent L protein inhibitors were analyzed. Based on the results, further molecular docking-based virtual screening of Selleckchem Nucleoside Analogue Library (156 compounds) was performed to find potential new inhibitors against the RVFV L protein. ADME (Absorption, Distribution, Metabolism, and Excretion) and toxicity analysis of these compounds was also performed. Besides, the binding mechanism and stability of identified compounds were confirmed by a 50 ns molecular dynamic (MD) simulation followed by MM/PBSA binding free energy calculations. Homology modeling determined a stable multi-domain structure of L protein. An analysis of known L protein inhibitors, including Monensin, Mycophenolic acid, and Ribavirin, provide insights into the binding mechanism and reveals key residues of the L protein binding pocket. The screening results revealed that the top three compounds, A-317491, Khasianine, and VER155008, exhibited a high affinity at the L protein binding pocket. ADME analysis revealed good pharmacodynamics and pharmacokinetic profiles of these compounds. Furthermore, MD simulation and binding free energy analysis endorsed the binding stability of potential compounds with L protein. In a nutshell, the present study determined potential compounds that may aid in the rational design of novel inhibitors of the RVFV L protein as anti-RVFV drugs.
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http://dx.doi.org/10.3390/ph15060659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9228520PMC
May 2022

Network Pharmacology Approach for Medicinal Plants: Review and Assessment.

Pharmaceuticals (Basel) 2022 May 4;15(5). Epub 2022 May 4.

Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia.

Natural products have played a critical role in medicine due to their ability to bind and modulate cellular targets involved in disease. Medicinal plants hold a variety of bioactive scaffolds for the treatment of multiple disorders. The less adverse effects, affordability, and easy accessibility highlight their potential in traditional remedies. Identifying pharmacological targets from active ingredients of medicinal plants has become a hot topic for biomedical research to generate innovative therapies. By developing an unprecedented opportunity for the systematic investigation of traditional medicines, network pharmacology is evolving as a systematic paradigm and becoming a frontier research field of drug discovery and development. The advancement of network pharmacology has opened up new avenues for understanding the complex bioactive components found in various medicinal plants. This study is attributed to a comprehensive summary of network pharmacology based on current research, highlighting various active ingredients, related techniques/tools/databases, and drug discovery and development applications. Moreover, this study would serve as a protocol for discovering novel compounds to explore the full range of biological potential of traditionally used plants. We have attempted to cover this vast topic in the review form. We hope it will serve as a significant pioneer for researchers working with medicinal plants by employing network pharmacology approaches.
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http://dx.doi.org/10.3390/ph15050572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9143318PMC
May 2022

Comprehensive computational analysis reveals H5N1 influenza virus-encoded miRNAs and host-specific targets associated with antiviral immune responses and protein binding.

PLoS One 2022 9;17(5):e0263901. Epub 2022 May 9.

Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan.

H5N1 virus (H5N1V) is highly contagious among birds and it was first detected in humans in 1997 during a poultry outbreak in Hong Kong. As the mechanism of its pathogenesis inside the host is still lacking, in this in-silico study we hypothesized that H5N1V might create miRNAs, which could target the genes associated with host cellular regulatory pathways, thus provide persistent refuge to the virus. Using bioinformatics approaches, several H5N1V produced putative miRNAs as well as the host genes targeted by these miRNAs were found. Functional enrichment analysis of targeted genes revealed their involvement in many biological pathways that facilitate their host pathogenesis. Eventually, the microarray dataset (GSE28166) was analyzed to validate the altered expression level of target genes and found the genes involved in protein binding and adaptive immune responses. This study presents novel miRNAs and their targeted genes, which upon experimental validation could facilitate in developing new therapeutics against H5N1V infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0263901PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9084522PMC
May 2022

Regulation of micro-RNA, epigenetic factor by natural products for the treatment of cancers: Mechanistic insight and translational association.

Saudi J Biol Sci 2022 Jun 10;29(6):103255. Epub 2022 Mar 10.

Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan.

From onset to progression, cancer is a ailment that might take years to grow. All common epithelial malignancies, have a long latency period, frequently 20 years or more, different gene may contain uncountable mutations if they are clinically detectable. MicroRNAs (miRNAs) are around 22nt non-coding RNAs that control gene expression sequence-specifically through translational inhibition or messenger degradation of RNA (mRNA). Epigenetic processes of miRNA control genetic variants through genomic DNA methylation, post-translation histone modification, rework of the chromatin, and microRNAs. The field of miRNAs has opened a new era in understanding small non-coding RNAs since discovering their fundamental mechanisms of action. MiRNAs have been found in viruses, plants, and animals through molecular cloning and bioinformatics approaches. Phytochemicals can invert the epigenetic aberrations, a leading cause of the cancers of various organs, and act as an inhibitor of these changes. The advantage of phytochemicals is that they only function on cells that cause cancer without affecting normal cells. Phytochemicals appear to play a significant character in modulating miRNA expression, which is linked to variations in oncogenes, tumor suppressors, and cancer-derived protein production, according to several studies. In addition to standard anti-oxidant or anti-inflammatory properties, the initial epigenetic changes associated with cancer prevention may be modulated by many polyphenols. In correlation with miRNA and epigenetic factors to treat cancer some of the phytochemicals, including polyphenols, curcumin, resveratrol, indole-3-carbinol are studied in this article.
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http://dx.doi.org/10.1016/j.sjbs.2022.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9052154PMC
June 2022

elucidation reveals potential phytochemicals against angiotensin-converting enzyme 2 (ACE-2) receptor to fight coronavirus disease 2019 (COVID-19).

Z Naturforsch C J Biosci 2022 Apr 25. Epub 2022 Apr 25.

Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan.

The coronavirus (SARS-CoV-2) pandemic is rapidly advancing and spreading worldwide, which poses an urgent need to develop anti-SARS-CoV-2 agents. A human receptor, namely, angiotensin-converting enzyme 2 (ACE-2), supports the SARS-CoV-2 entry, therefore, serves as a target for intervention via drug. In the current study, bioinformatic approaches were employed to screen potent bioactive compounds that might be ACE-2 receptor inhibitors. The employment of a docking study using ACE receptor protein with a ready-to-dock database of phytochemicals via MOE software revealed five compounds as potent molecules. Among them, astragaloside exhibited the highest binding affinity -21.8 kcal/mol and stable interactions within the active site of the ACE-2 receptor. Similarly, the phytochemicals such as pterocaryanin B, isoastragaloside II, and astraisoflavan glucoside followed by oleuropein showed a stronger binding affinity. We hypothesize these compounds as potential lead candidates for the development of anti- COVID-19 target-specific drugs.
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http://dx.doi.org/10.1515/znc-2021-0325DOI Listing
April 2022

Integrating Network Pharmacology and Molecular Docking Approaches to Decipher the Multi-Target Pharmacological Mechanism of L. Acting on Diabetes.

Pharmaceuticals (Basel) 2022 Mar 29;15(4). Epub 2022 Mar 29.

Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad 38000, Pakistan.

Type 2 diabetes mellitus (T2DM) is a notable health care load that imposes a serious impact on the quality of life of patients. The small amount of reported data and multiple spectra of pathophysiological mechanisms of T2DM make it a challenging task and serious economic burden in health care management. L. is a slender, perennial, deciduous, and woody twining plant used in various regions of Asia to treat a variety of ailments, including diabetes mellitus. Various in vitro studies revealed the therapeutic significance of against diabetes. However, the exact molecular mechanism remains unclarified. In the present study, a network pharmacology technique was employed to uncover the active ingredients, their potential targets, and signaling pathways in for the treatment of T2DM. In the framework of this study, we explored the active ingredient-target-pathway network and figured out that abrectorin, abrusin, abrisapogenol J, sophoradiol, cholanoic acid, precatorine, and cycloartenol decisively contributed to the development of T2DM by affecting AKT1, MAPK3, TNFalpha, and MAPK1 genes. Later, molecular docking was employed to validate the successful activity of the active compounds against potential targets. Lastly, we conclude that four highly active constituents, namely, abrusin, abrisapogenol J, precatorine, and cycloartenol, help in improving the body's sensitivity to insulin and regulate the expression of AKT1, MAPK3, TNFalpha, and MAPK1, which may act as potential therapeutic targets of T2DM. Integrated network pharmacology and docking analysis revealed that exerted a promising preventive effect on T2DM by acting on diabetes-associated signaling pathways. This provides a basis to understand the mechanism of the anti-diabetes activity of .
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http://dx.doi.org/10.3390/ph15040414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029140PMC
March 2022

Exploring the therapeutic potential of benzothiazine-pyrazole hybrid molecules against alpha-glucosidase: Pharmacological and molecular modelling based approach.

Saudi J Biol Sci 2022 Mar 24;29(3):1416-1421. Epub 2021 Nov 24.

Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Pakistan.

Diabetes mellitus (DM) is a metabolic disorder and a significant health problem all over the world. The current study elucidates the inhibitory potentials of the benzothiazine-pyrazole hybrid series against the α-Glucosidase enzyme. The molecular docking was employed to determine the binding affinity of synthetic compounds (ligands) with α-Glucosidase enzyme (receptor) active sites via the molecular operating environment (MOE). The molecular docking analysis revealed the best inhibitory interaction between certain synthetic compounds and the enzyme's active sites (α-Glucosidase). These compounds were further examined for drug-like properties, which necessarily validate the use of the compound as a drug. Then selected compounds were subjected to analysis to find the inhibitory potential with minimal dose. All compounds were docked into the active sites with the best binding pose and low rmsd values. The anti-diabetic analysis revealed that compound ST3 is more active against α-Glucosidase with IC values 5.8 µM as compared to acarbose which is 58.8 µM. The present study exhibited compound 2c has a high proficiency in lowering blood glucose levels compared to acarbose. This study strengthened the scope of designing/synthesizing these benzothiazine-pyrazole hybrid molecules as anti-diabetic drug molecules in the pharmaceutical industry.
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http://dx.doi.org/10.1016/j.sjbs.2021.11.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8913548PMC
March 2022

Exploring of novel 4-hydroxy-2H-benzo[e][1,2]thiazine-3-carbohydrazide 1,1-dioxide derivative as a dual inhibitor of α-glucosidase and α-amylase: Molecular docking, biochemical, enzyme kinetic and in-vivo mouse model study.

Int J Biol Macromol 2022 May 8;207:507-521. Epub 2022 Mar 8.

Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan. Electronic address:

Diabetes mellitus (DM) is a metabolic disorder that leads to hyperglycemia due to improper insulin secretion. The study aims to investigate the anti-diabetic potential of benzothiazine derivatives. Molecular docking and Molecular Dynamics simulation study revealed that Compound S6 (4-hydroxy-2H-benzo[e][1,2]thiazine-3-carbohydrazide 1,1-dioxide) and S7 (4-Hydroxy-2-methyl-2H-1,2-benzothiazine-3-carbohydrazide 1,1-dioxide) had less conformational changes during MD simulation analysis at 100 ns. Compound S6 and S7 showed potent activity with IC50 values of 5.93 μM, 6.91 μM and 75.17, 29.10 μM for α-glucosidase and α-amylase respectively and competitive type of inhibition was observed during enzyme kinetic study with a low value of Ki and Ki' for α-glucosidase and α-amylase, respectively. S6 has the lowest Ki (0.0736) and Ki' (-0.0982) for α-glucosidase. Furthermore, in vivo studies were carried out to distinguish the effects of the drug on the body. Histology analysis on mice model showed that compound S6 has a low necrosis rate in the liver, kidney, and pancreas compared to S7. Biochemical results of S6 revealed lower sugar level (112 mg/dL), increase insulin secretion (23, 25 μM/L), and low level of cholesterol (80, 85 mg/dL) and creatinine (1.6, 1.4 mg/dL). The results conclude that compound S6 is a new anti-diabetic agent that minimizes hyperglycemia complications.
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http://dx.doi.org/10.1016/j.ijbiomac.2022.03.023DOI Listing
May 2022

Proteome based mapping and molecular docking revealed DnaA as a potential drug target against .

Saudi J Biol Sci 2022 Feb 1;29(2):1147-1159. Epub 2021 Oct 1.

Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan.

is one of the major causes of diarrhea and remained a critical microbe responsible for higher morbidity and mortality rates resulting from dysentery every year across the world. Antibiotic therapy of Shigella diseases plays a critical role in decreasing the prevalence as well as the fatality rate of this infection. However, the management of these diseases remains challenging, owing to the overall increase in resistance against many antimicrobials. The situation necessitates the rapid development of effective and feasible treatments. In the present study, the subtractive genomics approach was utilized to find the potential drug targets for strain Ss046. Various tools of bioinformatics were implemented to remove the human-specific homologous and pathogen-specific paralogous sequences from the bacterial proteome. Then, metabolic pathway and subcellular location analysis were performed of essential bacterial proteins to describe their role in various cellular processes. Only one essential protein i-e Chromosomal replication initiator protein DnaA was found in the proteome of the pathogen that could be used as a potent target for designing new drugs. 3D structure prediction of DnaA protein was carried out using Phyre 2. Molecular docking of 5000 phytochemicals was performed against DnaA to identify four top-ranked phytochemicals (Riccionidin A, Dothistromin, Fustin, and Morin) based on scoring functions and interaction with the active site. This study suggests that these phytochemicals could be used as antibacterial drugs to treat infections in the future. To confirm their efficacy and evaluate their drug potency, further in vitro analyses are required.
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http://dx.doi.org/10.1016/j.sjbs.2021.09.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8886675PMC
February 2022

The Insight of In Silico and In Vitro evaluation of Beta vulgaris phytochemicals against Alzheimer's disease targeting acetylcholinesterase.

PLoS One 2022 3;17(3):e0264074. Epub 2022 Mar 3.

Department of Life Sciences, University of Management and Technology, Lahore, Pakistan.

B. vulgaris extracts possess antioxidant, anti-inflammatory along with its role in improving memory disorders. Subsequently, in vitro and in silico studies of its purified phytochemicals may expand complementary and alternative Alzheimer's therapeutic option. Super activation of acetylcholinesterase enzyme is associated explicitly with Alzheimer's disease (AD) ultimately resulting in senile dementia. Hence, acetylcholinesterase enzyme inhibition is employed as a promising approach for AD treatment. Many FDA approved drugs are unable to cure the disease progression completely. The Present study was devised to explore the potential bioactive phytochemicals of B. vulgaris as alternative therapeutic agents against AD by conducting in vitro and in silico studies. To achieve this, chemical structures of phytochemicals were recruited from PubChem. Further, these compounds were analyzed for their binding affinities towards acetylcholinesterase (AChE) enzyme. Pharmacophoric ligand-based models showed major characteristics like, HBA, HBD, hydrophobicity, aromaticity and positively ionizable surface morphology for receptor binding. Virtual screening identified three hit compounds including betanin, myricetin and folic acid with least binding score compared to the reference drug, donepezil (-17 kcal/mol). Further, in vitro studies for anti-acetylcholinesterase activity of betanin and glycine betaine were performed. Dose response analysis showed 1.271 μM and 1.203 μM 50% inhibitory concentration (IC50) values for betanin and glycine betaine compounds respectively. Our findings indicate that phytoconstituents of B. vulgaris can be implicated as an alternative therapeutic drug candidate for cognitive disorders like Alzheimer's disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0264074PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8893657PMC
March 2022

Proteome based mapping and reverse vaccinology techniques to contrive multi-epitope based subunit vaccine (MEBSV) against Streptococcus pyogenes.

Infect Genet Evol 2022 06 26;100:105259. Epub 2022 Feb 26.

Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Pakistan. Electronic address:

Streptococcus pyogenes is a root cause of human infection like pharyngitis, tonsillitis, scarlet fever, impetigo, and respiratory tract infections. About 11 million individuals in the US suffer from pharyngitis every year. Unfortunately, no vaccine against S. pyogenes is available yet. The purpose of this study is to create a multiepitope-based subunit vaccine (MEBSV) targeting S. pyogenes top four highly antigenic proteins by using a combination of immunological techniques and molecular docking to tackle term group A streptococcal (GAS) infections. T-cell (HTL & CTL), B-cell, and IFN-γ of target proteins were forecasted and epitopes having high antigenic properties being selected for subsequent research. For designing of final vaccine, 5LBL, 9CTL, and 4HTL epitopes were joined by the KK, AAY, and GPGPG linkers. To enhance the immune response, the N-end of the vaccine was linked by adjuvant (Cholera enterotoxin subunit B) with a linker named EAAAK. With the addition of adjuvants and linkers, the construct size was 421 amino acids. IFN-γ and B-cell epitopes illustrate that the modeled construct is optimized for cell-mediated immune or humoral responses. The developed MEBSV structure was assessed to be highly antigenic, non-toxic, and non-allergenic. Moreover, disulphide engineering further enhanced the stability of the final vaccine protein. Molecular docking of the MEBSV with toll-like receptor 4 (TLR4) was conducted to check the vaccine's compatibility with the receptor. Besides, in-silico cloning has been carried out for credibility validation and proper expression of vaccine construct. These findings suggested that the multi-epitope vaccine produced might be a potential immunogenic against Group A streptococcus infections but further experimental testing is required to validate this study.
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http://dx.doi.org/10.1016/j.meegid.2022.105259DOI Listing
June 2022

Identification of Cyclic Sulfonamides with an Arylacetamide Group as α-Glucosidase and α-Amylase Inhibitors: Biological Evaluation and Molecular Modeling.

Pharmaceuticals (Basel) 2022 Jan 17;15(1). Epub 2022 Jan 17.

Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia.

Diabetes mellitus (DM), a complicated metabolic disorder, is due to insensitivity to insulin function or reduction in insulin secretion, which results in postprandial hyperglycemia. α-Glucosidase inhibitors (AGIs) and α-amylase inhibitors (AAIs) block the function of digestive enzymes, which delays the carbohydrate hydrolysis process and ultimately helps to control the postprandial hyperglycemia. Diversified 2-(3-(3-methoxybenzoyl)-4-hydroxy-1,1-dioxido-2-benzo[][1,2]thiazin-2-yl)--arylacetamides were synthesized and evaluated for their in vitro inhibitory potential against α-glucosidase and α-amylase enzymes. The compounds with chloro, bromo and methyl substituents demonstrated good inhibition of α-glucosidase enzymes having IC values in the range of 25.88-46.25 μM, which are less than the standard drug, acarbose (IC = 58.8 μM). Similarly, some derivatives having chloro, bromo and nitro substituents were observed potent inhibitors of α-amylase enzyme, with IC values of 7.52 to 15.06 μM, lower than acarbose (IC = 17.0 μM). In addition, the most potent compound, -(4-bromophenyl)-2-(4-hydroxy-3-(3-methoxybenzoyl)-1,1-dioxido-2-benzo[e][1,2]thiazin-2-yl)acetamide (), was found to be a non-competitive and competitive inhibitor of α-glucosidase and α-amylase enzymes, respectively, during kinetic studies. The molecular docking studies provided the binding modes of active compounds and the molecular dynamics simulation studies of compound in complex with α-amylase also showed that the compound is binding in a fashion similar to that predicted by molecular docking studies.
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http://dx.doi.org/10.3390/ph15010106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8777765PMC
January 2022

Designing of a multi-epitopes-based peptide vaccine against rift valley fever virus and its validation through integrated computational approaches.

Comput Biol Med 2022 02 17;141:105151. Epub 2021 Dec 17.

Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia. Electronic address:

Since its discovery, the Rift Valley Fever virus (RVFV) has been the source of numerous outbreaks in the Arab Peninsulas and Africa, wreaking havoc on humans and animals. The lack of therapeutics or licensed human vaccines limits the options for controlling RVFV outbreaks. Therefore, RVFV has been prioritized for rapid research and innovation of prevention strategies to control and prevent its outbreaks. The purpose of this study was to design a multi-epitope-based peptide vaccine (MEBPV) against RVFV. Bioinformatics approaches were used to design a potent MEBPV that can potentially activate both CD8 and CD4 T-cell immune responses, and several computational tools were employed to investigate its biological activities. Three antigenic proteins (Nucleocapsid (N), Glycoprotein C (GC), and Glycoprotein N (GN)) from the RVFV were chosen and potential immunogenic T- and B -cell epitopes were predicted from them. Based on in silico analysis, a MEBPV based on highly scored T and B-cell epitopes (6 CTL, 5 HTL, and 4 LBL) combined with linkers and adjuvants was developed. The finest predicted model was used for docking studies with Toll-like receptors (TLR3 and TLR8) and MHC molecules (MHC I and MHC II) after predicting and analyzing the tertiary structure of MEBPV. The designed MEBPV was then tested for stability with TLR3 and TLR8 receptors using molecular dynamics (MD) simulation and MMGBSA analysis. The MEBPV -TLR3, MEBPV -TLR8, MEBPV-MHC I and MEBPV -MHC II docked models were found stable during simulation time in MD and MMGBSA studies. In silico analysis revealed that the constructed vaccine could elicit both cell-mediated and humoral immune responses simultaneously. The proposed MEBPV could be a strong candidate against RVFV, but it will need to be tested in the laboratory to guarantee its safety and immunogenicity.
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http://dx.doi.org/10.1016/j.compbiomed.2021.105151DOI Listing
February 2022

Subtractive genomics and molecular docking approach to identify drug targets against Stenotrophomonas maltophilia.

PLoS One 2021 15;16(12):e0261111. Epub 2021 Dec 15.

Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan.

Stenotrophomonas maltophilia is a multidrug resistant pathogen associated with high mortality and morbidity in patients having compromised immunity. The efflux systems of S. maltophilia include SmeABC and SmeDEF proteins, which assist in acquisition of multiple-drug-resistance. In this study, proteome based mapping was utilized to find out the potential drug targets for S. maltophilia strain k279a. Various tools of computational biology were applied to remove the human-specific homologous and pathogen-specific paralogous sequences from the bacterial proteome. The CD-HIT analysis selected 4315 proteins from total proteome count of 4365 proteins. Geptop identified 407 essential proteins, while the BlastP revealed approximately 85 non-homologous proteins in the human genome. Moreover, metabolic pathway and subcellular location analysis were performed for essential bacterial genes, to describe their role in various cellular processes. Only two essential proteins (Acyl-[acyl-carrier-protein]-UDP-N acetyl glucosamine O-acyltransferase and D-alanine-D-alanine ligase) as candidate for potent targets were found in proteome of the pathogen, in order to design new drugs. An online tool, Swiss model was employed to model the 3D structures of both target proteins. A library of 5000 phytochemicals was docked against those proteins through the molecular operating environment (MOE). That resulted in to eight inhibitors for both proteins i.e. enterodiol, aloin, ononin and rhinacanthinF for the Acyl-[acyl-carrier-protein]-UDP-N acetyl glucosamine O-acyltransferase, and rhazin, alkannin beta, aloesin and ancistrocladine for the D-alanine-D-alanine ligase. Finally the ADMET was done through ADMETsar. This study supported the development of natural as well as cost-effective drugs against S. maltophilia. These inhibitors displayed the effective binding interactions and safe drug profiles. However, further in vivo and in vitro validation experiment might be performed to check their drug effectiveness, biocompatibility and their role as effective inhibitors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0261111PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673605PMC
January 2022

In-silico modeling and in-vitro studies of 2,1-benzothiazine-2,2-dioxide based hydrazone derivatives as α-glucosidase inhibitors.

Pak J Pharm Sci 2021 Sep;34(5(Supplementary)):1951-1955

Department of Chemistry, Government College University, Faisalabad, Pakistan.

Diabetes mellitus (DM) is a metabolic disorder characterized by frequent urination, hunger and high blood sugar level. α-glucosidase inhibitors are considered as a frontline treatment for the DM. This research article deals with the identification of benzothiazine derivatives as α-glucosidase inhibitors through in-silico techniques and then the confirmation through in-vitro analysis. Molecular docking studies were carried out to find out the binding interactions of targeted molecules with receptor molecule i.e., α-glucosidase enzyme. The synthetic compounds 1 (a-n), 2 (a-d) and 3 (a-b) were evaluated for in-vitro alpha glucosidase inhibitory activities that resulted in the discovery of various potent molecules. Majority of the compounds (1c, 1f, 1g, 1k-n, 2a-d and 3a-b) exhibited good inhibitory activity against α-glucosidase. Compounds 1c, 1g, 1k and 1m appeared as the potent active compounds with the IC values 17.44, 27.64, 24.43, 42.59 and 16.90 μM respectively. Compounds 1c & 2c were found almost 3-folds more active than the standard acarbose. The study may lead to discover potent drug candidates with less complication for the treatment of the type II diabetes mellitus.
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September 2021

Synthesis and α-glucosidase inhibition studies of norfloxacin-acetanilide hybrids.

Pak J Pharm Sci 2021 Sep;34(5(Supplementary)):1909-1915

Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam Campus, Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia/Atta-ur-Rahman Institute for Natural Products Discovery (AuRIns), Universiti Teknologi MARA, Puncak Alam Campus, Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia.

α-Glucosidase inhibitors occupy a prominent position among the various treatments of type-2 diabetes mellitus (DM2). In this study, a series of new norfloxacin-acetanilide hybrid molecules were synthesized and screened for α-glucosidase inhibition activity. The synthetic methodology involves the synthesis of a series of α-bromoacetanilides by condensing bromoacetyl bromide with various substituted anilines. These α-bromoacetanilides were coupled with norfloxacin in DMF to get the titled hybrids. The structure elucidation of synthesized compounds were characterized by H NMR, C NMR and LC-MS. Finally, the compounds were screened for their α-glucosidase inhibition activity using acarbose as a reference drug (IC =58 μM). Among the tested compounds, 3i and 3j displayed potent α-glucosidase inhibition activity with IC values of 7.81±0.038 and 5.55±0.012 μM respectively. In-addition, 3m, 3f and 3k were demonstrated moderate alpha-glucosidase inhibition activities with IC values of 52.905±0.041, 23.79± 0.087 and 23.06±0.026 μM respectively. The structure-activity relationship was established with the help of molecular docking by using Molecular Operating Environment software (MOE 2014).
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September 2021

Development of a Candidate Multi-Epitope Subunit Vaccine against : Subtractive Proteomics and Immuno-Informatics Approach.

Vaccines (Basel) 2021 Nov 22;9(11). Epub 2021 Nov 22.

Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad 38000, Pakistan.

is a Gram-negative bacterium which has gained considerable importance in recent years. It is involved in 10% of nosocomial and community-acquired urinary tract infections and 12% of hospital-acquired pneumonia. This organism has an intrinsic ability to produce inducible chromosomal AmpC beta-lactamases, which confer high resistance. The drug resistance in has been reported in China, Israel, Poland, Italy and the United States, with a high mortality rate (~50%). This study aims to combine immunological approaches with molecular docking approaches for three highly antigenic proteins to design vaccines against . The synthesis of the B-cell, T-cell (CTL and HTL) and IFN-γ epitopes of the targeted proteins was performed and most conserved epitopes were chosen for future research studies. The vaccine was predicted by connecting the respective epitopes, i.e., B cells, CTL and HTL with KK, AAY and GPGPG linkers and all these were connected with N-terminal adjuvants with EAAAK linker. The humoral response of the constructed vaccine was measured through IFN-γ and B-cell epitopes. Before being used as vaccine candidate, all identified B-cell, HTL and CTL epitopes were tested for antigenicity, allergenicity and toxicity to check the safety profiles of our vaccine. To find out the compatibility of constructed vaccine with receptors, MHC-I, followed by MHC-II and TLR4 receptors, was docked with the vaccine. Lastly, in order to precisely certify the proper expression and integrity of our construct, in silico cloning was carried out. Further studies are needed to confirm the safety features and immunogenicity of the vaccine.
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http://dx.doi.org/10.3390/vaccines9111373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624419PMC
November 2021

SNP of HMGCR and Apo E genes and their impact in response to statin therapy in hypercholesterolemic and hypertriglyceridemic patients in Pakistan.

Pak J Pharm Sci 2021 Jul;34(4(Supplementary)):1577-1583

Fish Nutrition Lab., Department of Zoology, Government College University, Faisalabad, Pakistan.

Coronary artery disease (CAD) and the problems associated with it are the most prominent causes of death in the whole world. Statins are accustomed to lower lipid levels in CAD patients. The target of this study was to analyze whether or not common variations in HMGCoA Reductase (HMGCR) and Apolipoprotein E (ApoE) genes are responsible for metabolism of lipid and statin that modify the impact of statins on serum level of lipids and lipoprotein concentrations in Coronary heart disease patients. One hundred CAD patients were registered for the study. At the start of the study biochemical measurements were performed to work out the baseline levels. Patients were treated with twenty mg Lipitor for one month and biochemical measurements were tested again. According to the post-treatment, LDL-c levels, patients were divided into a pair of group as non-responders and responders, independently. The information concerning the risk factors like smoking, alcohol consumption etc. was conjointly obtained. DNA was extracted from peripheral blood. The presence of rs17244841 and rs17238540 mutations in HMGCR and έ2, έ3 and έ4 variants of ApoE were settled by performing RT-PCR. Results were assessed statistically. HMGCR mutations were principally found in responders and ε4 variant of ApoE was principally found in non-responders. It was found that the presence of HMGCR mutations causes a big reduction in total cholesterol and LDL-c levels. Conjointly, the presence of έ2 variant of Apo E causes a statistically vital increase in triglyceride levels. Our findings should be investigated by different researchers to clarify the mechanism.
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July 2021

In Silico Core Proteomics and Molecular Docking Approaches for the Identification of Novel Inhibitors against .

Int J Environ Res Public Health 2021 10 28;18(21). Epub 2021 Oct 28.

Plant Production Department, College Food and Agricultural Sciences, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia.

is a significant pathogen that causes skin and upper respiratory tract infections and non-suppurative complications, such as acute rheumatic fever and post-strep glomerulonephritis. Multidrug resistance has emerged in strains, making them more dangerous and pathogenic. Hence, it is necessary to identify and develop therapeutic methods that would present novel approaches to infections. In the current study, a subtractive proteomics approach was employed to core proteomes of four strains of using several bioinformatic software tools and servers. The core proteome consists of 1324 proteins, and 302 essential proteins were predicted from them. These essential proteins were analyzed using BLASTp against human proteome, and the number of potential targets was reduced to 145. Based on subcellular localization prediction, 46 proteins with cytoplasmic localization were chosen for metabolic pathway analysis. Only two cytoplasmic proteins, i.e., chromosomal replication initiator protein DnaA and two-component response regulator (TCR), were discovered to have the potential to be novel drug target candidates. Three-dimensional (3D) structure prediction of target proteins was carried out via the Swiss Model server. Molecular docking approach was employed to screen the library of 1000 phytochemicals against the interacting residues of the target proteins through the MOE software. Further, the docking studies were validated by running molecular dynamics simulation and highly popular binding free energy approaches of MM-GBSA and MM-PBSA. The findings revealed a promising candidate as a novel target against infections.
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http://dx.doi.org/10.3390/ijerph182111355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8582943PMC
October 2021

Rational design of chimeric Multiepitope Based Vaccine (MEBV) against human T-cell lymphotropic virus type 1: An integrated vaccine informatics and molecular docking based approach.

PLoS One 2021 27;16(10):e0258443. Epub 2021 Oct 27.

Department of Microbiology, Government College University Faisalabad, Faisalabad, Pakistan.

Human T-cell lymphotropic virus type 1 (HTLV-1) is an infectious virus that has been linked to adult T cell leukemia /lymphoma, aggressive CD4-T cell malignancy and many other immune-related medical illnesses. So far, no effective vaccine is known to combat HTLV-1, hence, the current research work was performed to design a potential multi-epitope-based subunit vaccine (MEBV) by adopting the latest methodology of reverse vaccinology. Briefly, three highly antigenic proteins (Glycoprotein, Accessory protein, and Tax protein) with no or minimal (<37%) similarity with human proteome were sorted out and potential B- and T-cell epitopes were forecasted from them. Highly antigenic, immunogenic, non-toxic, non-allergenic and overlapping epitopes were short-listed for vaccine development. The chosen T-cell epitopes displayed a strong binding affinity with their corresponding Human Leukocyte Antigen alleles and demonstrated 95.8% coverage of the world's population. Finally, nine Cytotoxic T Lymphocytes, six Helper T Lymphocytes and five Linear B Lymphocytes epitopes, joint through linkers and adjuvant, were exploited to design the final MEBV construct, comprising of 382 amino acids. The developed MEBV structure showed highly antigenic properties while being non-toxic, soluble, non-allergenic, and stable in nature. Moreover, disulphide engineering further enhanced the stability of the final vaccine protein. Additionally, Molecular docking analysis and Molecular Dynamics (MD) simulations confirmed the strong association between MEBV construct and human pathogenic immune receptor TLR-3. Repeated-exposure simulations and Immune simulations ensured the rapid antigen clearance and higher levels of cell-mediated immunity, respectively. Furthermore, MEBV codon optimization and in-silico cloning was carried out to confirm its augmented expression. Results of our experiments suggested that the proposed MEBV could be a potential immunogenic against HTLV-1; nevertheless, additional wet lab experiments are needed to elucidate our conclusion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0258443PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550388PMC
November 2021

Proteome-Wide Mapping and Reverse Vaccinology Approaches to Design a Multi-Epitope Vaccine against .

Vaccines (Basel) 2021 Sep 26;9(10). Epub 2021 Sep 26.

Department of Bioinformatics and Biotechnology, Government College University, Faisalabad 38000, Pakistan.

is a highly versatile bacteria of livestock and humans, causing enteritis (a common food-borne illness in humans), enterotoxaemia (in which toxins are formed in the intestine which damage and destroy organs, i.e., the brain), and gangrene (wound infection). There is no particular cure for the toxins of . Supportive care (medical control of pain, intravenous fluids) is the standard treatment. Therefore, a multiple-epitope vaccine (MEV) should be designed to battle against infection. Furthermore, the main objective of this in silico investigation is to design an MEV that targets . For this purpose, we selected the top three proteins that were highly antigenic using immuno-informatics approaches, including molecular docking. B-cells, IFN-gamma, and T cells for target proteins were predicted and the most conserved epitopes were selected for further investigation. For the development of the final MEV, epitopes of LBL5, CTL17, and HTL13 were linked to GPGPG, AAY, and KK linkers. The vaccine N-end was joined to an adjuvant through an EAAK linker to improve immunogenicity. After the attachment of linkers and adjuvants, the final construct was 415 amino acids. B-cell and IFN-gamma epitopes demonstrate that the model structure is enhanced for humoral and cellular immune responses. To validate the immunogenicity and safety of the final construct, various physicochemical properties, and other properties such as antigenicity and non-allergens, were evaluated. Furthermore, molecular docking was carried out for verification of vaccine compatibility with the receptor, evaluated in silico. Also, in silico cloning was employed for the verification of the proper expression and credibility of the construct.
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http://dx.doi.org/10.3390/vaccines9101079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8539331PMC
September 2021

Disease-associated variants of Gap Junction Beta 2 protein (GJB2) in the deaf population of Southern Punjab of Pakistan.

PLoS One 2021 25;16(10):e0259083. Epub 2021 Oct 25.

Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan.

Hearing impairment (HI) is a highly heterogeneous genetic disorder and is classified into nonsyndromic (without any other clinical manifestations) and syndromic (if combined with other clinical presentations) forms. Variations in GJB2 gene are the leading cause of autosomal recessive nonsyndromic hearing loss (ARNSHL) in several populations worldwide. This study was carried out to investigate the prevalence of GJB2 variations in severe-to-profound hearing impaired families of Southern Punjab of Pakistan. Ten families segregating ARNSHL were recruited from different areas of the region. Sanger sequencing of GJB2 coding region was carried out. In two out of ten families, NM_004004:c.*71G>A (p.(Trp24*)) and NM_004004:c.358_360del (p.(Glu120del)) homozygous variants were identified as the cause of hearing loss. Our study showed that GJB2-related hearing loss accounts for at least 20% of all cases with severe-to-profound hearing loss in the Southern Punjab population of Pakistan.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0259083PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8544867PMC
December 2021

Implementation of Vaccinomics and In-Silico Approaches to Construct Multimeric Based Vaccine Against Ovarian Cancer.

Int J Pept Res Ther 2021 19;27(4):2845-2859. Epub 2021 Oct 19.

Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan.

One of the most common gynecologic cancers is ovarian cancer and ranked third after the other two most common cancers: cervical and uterine. The highest mortality rate has been observed in the case of ovarian cancer. To treat ovarian cancer, an immune-informatics approach was used to design a multi-epitope vaccine (MEV) structure. Epitopes prediction of the cancer testis antigens (NY-ESO-1), A-Kinase anchor protein (AKAP4), Acrosin binding protein (ACRBP), Piwi-like protein (PIWIL3), and cancer testis antigen 2 (LAGE-1) was done. Non-toxic, highly antigenic, non-allergenic, and overlapping epitopes were shortlisted for vaccine construction. Chosen T-cell epitopes displayed a robust binding attraction with their corresponding Human Leukocyte Antigen (HLA) alleles demonstrated 97.59% of population coverage. The vaccine peptide was established by uniting three key constituents, comprising the 14 epitopes of CD8 + cytotoxic T lymphocytes (CTLs), 5 helper epitopes, and the adjuvant. For the generation of the effective response of CD4 + cells towards the T-helper cells, granulocyte-macrophage-colony-stimulating factor (GM-CSF) was applied. With the addition of adjuvants and linkers, the construct size was 547 amino acids. The developed MEV structure was predicted to be antigenic, non-toxic, non-allergenic, and firm in nature. I-tasser anticipated the 3D construction of MEV. Moreover, disulfide engineering further enhanced the stability of the final vaccine protein. In-silico cloning and vaccine codon optimization were done to analyze the up-regulation of its expression. The outcomes established the vaccine's immunogenicity and safety profile, besides its aptitude to encourage both humoral and cellular immune responses. The offered vaccine, grounded on our in-silico investigation, may be considered for ovarian cancer immunotherapy.

Supplementary Information: The online version contains supplementary material available at 10.1007/s10989-021-10294-w.
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http://dx.doi.org/10.1007/s10989-021-10294-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524215PMC
October 2021

Designing a Multi-Epitope Vaccine against by Employing Integrated Core Proteomics, Immuno-Informatics and In Silico Approaches.

Biology (Basel) 2021 Oct 3;10(10). Epub 2021 Oct 3.

Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia.

, a Gram-negative bacterium that infects the rectum, urethra, congenital sites, and columnar epithelium of the cervix. It is a major cause of preventable blindness, ectopic pregnancy, and bacterial sexually transmitted infections worldwide. There is currently no licensed multi-epitope vaccination available for this pathogen. This study used core proteomics, immuno-informatics, and subtractive proteomics approaches to identify the best antigenic candidates for the development of a multi-epitope-based vaccine (MEBV). These approaches resulted in six vaccine candidates: Type III secretion system translocon subunit CopD2, SctW family type III secretion system gatekeeper subunit CopN, SycD/LcrH family type III secretion system chaperone Scc2, CT847 family type III secretion system effector, hypothetical protein CTDEC_0668, and CHLPN 76kDa-like protein. A variety of immuno-informatics tools were used to predict B and T cell epitopes from vaccine candidate proteins. An in silico vaccine was developed using carefully selected epitopes (11 CTL, 2 HTL & 10 LBL) and then docked with the MHC molecules (MHC I & MHC II) and human TLR4. The vaccine was coupled with Cholera toxin subunit B (CTB) adjuvant to boost the immune response. Molecular dynamics (MD) simulations, molecular docking, and MMGBSA analysis were carried out to analyze the molecular interactions and binding affinity of MEBV with TLR4 and MHC molecules. To achieve the highest level of vaccine protein expression, the MEBV was cloned and reverse-translated in . The highest level of expression was achieved, and a CAI score of 0.97 was reported. Further experimental validation of the MEBV is required to prove its efficacy. The vaccine developed will be useful in preventing infections caused by .
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http://dx.doi.org/10.3390/biology10100997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533590PMC
October 2021

Identifying key genes and screening therapeutic agents associated with diabetes mellitus and HCV-related hepatocellular carcinoma by bioinformatics analysis.

Saudi J Biol Sci 2021 Oct 30;28(10):5518-5525. Epub 2021 Jul 30.

Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Allama Iqbal Road, Faisalabad-38000, Pakistan.

Objective: Incidence of both Type 2 diabetes mellitus (T2DM) and hepatocellular carcinoma (HCC) are rapidly increasing worldwide. One of the leading causes of HCC is hepatitis C virus (HCV), which is a resource of blood-borne viral infection. HCV increases the risk for HCC probably by promoting fibrosis and cirrhosis. Association among T2DM and HCV related HCC remains significant, indicating that such association is clinically reliable and robust. Lawson was the first who uncovered HCC in person suffered from T2DM. Until now, genetic association between HCV related HCC and T2DM is poorly known. Current work was designed to figure out the molecular mechanisms of both diseases by identifying the hub genes and therapeutic drugs using integrated bioinformatics analysis.

Methods: Four microarray datasets were downloaded from GEO database and analyzed using R in order to obtain different expressed genes (DEGs). Protein-protein interaction (PPI) networks was constructed using STRING tool and visualized by Cytoscape. Moreover, hub genes were identified on the basis of their degree of connectivity. Finally, Networkanalyst and DGIdb were used for the identification of transcription factors (TFs) and selection of candidate drugs, respectively.

Results: A total of 53 DEGs were identified, of which 41 were upregulated genes and 12 were downregulated genes. PPI network obtained from STRING were subjected to Cytoscape plugin cytoHubba, and top 10 genes (AURKA, JUN, AR, MELK, NCOA2, CENPF, NCAPG, PCK1, RAD51AP1, and GTSE1) were chosen as the target hub genes based on the highest degree of connectivity. Furthermore, 47 drugs of AURKA, JUN, AR, MELK, and NCOA2 were found having therapeutic potential to treat HCV-HCC in patients with T2DM.

Conclusion: This study updates the information and yield a new perspective in context of understanding the pathogenesis and development of HCV related HCC in affected persons with T2DM.  and  investigation of hub genes and pathway interaction is essential to delineate the specific roles of the novel hub genes, which may help to reveal the genetic association between HCV-HCC and T2DM. In future, hub genes along with their candidate drugs might be capable of improving the personalized detection and therapies for both diseases.
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http://dx.doi.org/10.1016/j.sjbs.2021.07.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459114PMC
October 2021

Discovery of Amide-Functionalized Benzimidazolium Salts as Potent α-Glucosidase Inhibitors.

Molecules 2021 Aug 6;26(16). Epub 2021 Aug 6.

Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia.

α-Glucosidase inhibitors (AGIs) are used as medicines for the treatment of diabetes mellitus. The α-Glucosidase enzyme is present in the small intestine and is responsible for the breakdown of carbohydrates into sugars. The process results in an increase in blood sugar levels. AGIs slow down the digestion of carbohydrates that is helpful in controlling the sugar levels in the blood after meals. Among heterocyclic compounds, benzimidazole moiety is recognized as a potent bioactive scaffold for its wide range of biologically active derivatives. The aim of this study is to explore the α-glucosidase inhibition ability of benzimidazolium salts. In this study, two novel series of benzimidazolium salts, i.e., 1-benzyl-3-{2-(substituted) amino-2-oxoethyl}-1-benzo[]imidazol-3-ium bromide - and 1-benzyl-3-{2-substituted) amino-2-oxoethyl}-2-methyl-1-benzo[] imidazol-3-ium bromide - were screened for their in vitro α-glucosidase inhibitory potential. These compounds were synthesized through a multistep procedure and were characterized by -NMR, C-NMR, and EI-MS techniques. Compound was identified as the potent α-glucosidase inhibitor among the series with an IC value of 14 ± 0.013 μM, which is 4-fold higher than the standard drug, acarbose. In addition, compounds , , , , , , and also exhibited pronounced potential for α-glucosidase inhibition with IC value ranging from 15 ± 0.037 to 32.27 ± 0.050 µM when compared with the reference drug acarbose (IC = 58.8 ± 0.12 μM). A molecular docking study was performed to rationalize the binding interactions of potent inhibitors with the active site of the α-glucosidase enzyme.
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http://dx.doi.org/10.3390/molecules26164760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400806PMC
August 2021

Discovery of Novel HCV NS5B polymerase inhibitor, 2-(3,4-dimethyl-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]thiazin-2(4H)-yl)-N-(2-fluorobenzyl)acetamide via molecular docking and experimental approach.

Clin Exp Pharmacol Physiol 2021 12 6;48(12):1653-1661. Epub 2021 Sep 6.

Department of Chemistry, Government College University, Faisalabad, Pakistan.

Hepatitis C Virus (HCV) is a viral infection posing a severe global threat that left untreated progresses to end-stage liver disease, including cirrhosis and hepatocellular carcinoma (HCC). Moreover, no prophylactic approach exists so far enabling its prevention. The NS5B polymerase holds special significance as the target of intervention against HCV infection. The current study kindles benzothiazine derivatives against HCV NS5B polymerase through in silico and experimental approaches. Following docking, the compound 2-(3,4-dimethyl-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]thiazin-2(4H)-yl)-N-(2-fluorobenzyl)acetamide was revealed to form effective binding interaction in the proposed site of HCV NS5B with a score of -10 kcal/mol and subsequently was deciphered through molecular dynamics (MD) simulation study which indicated interaction of residues TYR_382, VAL_381 and HIS_467 through hydrophobic interaction and two residues such as GLU_202 and LYS_209 contributed in the formation of water bridges. The subsequent in silico pharmacological analysis revealed its safe drug profile. The cytotoxicity activity of compound 6c indicated to be non-toxic in HepG2 cells at concentration ranges from 0.001-1.0 µmol/L with >80% cell viability and diminished expression of the HCV NS5B to 98% at the dose of 1.0 µmol/L and 90% at 0.5µmol/L. Thus the hit compound 6c might be a potent NS5B polymerase inhibitor required to be validated further through in vivo and preclinical studies.
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http://dx.doi.org/10.1111/1440-1681.13571DOI Listing
December 2021

Synthesis and Therapeutic Potential of Nanoceria against Cancer: An Update.

Crit Rev Ther Drug Carrier Syst 2021 ;38(5):1-26

Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan.

Applications of nanoceria in the biomedical field are quite promising, as previous data has shown potential use of nanoceria as therapeutics via radical scavenging and oxidative stress mitigating properties. But, still, there are contradicting reports regarding nanoceria activity, mode of action, and in vitro toxicity in the cell. There are different nanoceria synthesis methods and Ligands for functionalization and loading of nanoceria into drugs for targeted drug delivery. Redox chemistry of nanoceria exerts their anticancer properties through apoptosis and oxidative stress as it can switch between Ce3+ and Ce4+ and act as free radical scavengers. For breast cancer treatment, cerium oxide nanoparticles (CeONPs) can act as protectant for healthy cells against on-going radiotherapy. Similarly, CeONPs were used to make pancreatic cancer cells more sensitive to radiation damage setting them on the apoptotic pathway. Herein, the study reflects the use of nanoceria as a drug delivery system in chemotherapy due to its efficiency in acidic pH and oxidase activity in the microenvironment. A controlled drug delivery system was adapted using a nano-complexes of AMD-GCCNP-DOX, which were then employed against the retinoblastoma cells from the human eye to target the overexpressing chemokine receptor 4 (CXCR4). In radiotherapy, nanoceria acts as radioprotectants due to their free radical scavenging property and inhibit the proliferation and migration of gastric cancer. This paper summarizes the synthesis methods and application of nanoceria in cancer.
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http://dx.doi.org/10.1615/CritRevTherDrugCarrierSyst.2021037662DOI Listing
October 2021

Role of Heavy Metals in Diabetes: Mechanisms and Treatment Strategies.

Crit Rev Eukaryot Gene Expr 2021 ;31(3):65-80

Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan.

Toxic metals affecting metabolic pathways have a broad range in the ecosystem from both natural and anthropogenic sources. Because of constant contamination from waste and untreated chemical effluents, their emissions have risen significantly over the last few decades, quickly gaining attention due to their crucial role in the development of several metabolic disorders, notably diabetes mellitus. Cadmium and arsenic not only spread widely in our atmosphere but are also linked to a wide range of health hazards. These are primarily accumulated in the liver, kidney, and pancreas once they reach the human body, where they have deleterious effects on the metabolism of glucose and its association with other metabolic pathways, particularly glycolysis, glycogenesis, and gluconeogenesis, by altering and impairing the specific activity of major enzymes. Impairment of hepatic glucose homeostasis plays a crucial role in diabetes mellitus pathogenesis. Impaired liver and kidney functions, as well as decreased pancreatic and muscle function, also contribute significantly to elevated levels of blood glucose. Heavy metals have the potential to cause changes in the conformation in these enzymes. They also impair hormonal balance by destroying the pancreas and adrenal glands. Such metals often facilitate the development of reactive oxygen species and inhibit antioxidant defense mechanisms, with multiple organs subsequently damaged. This review briefly discusses the involvement of heavy metals in metabolic disorders such as diabetes mellitus, the enzymes involved in this pathway, and glucose homeostasis.
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http://dx.doi.org/10.1615/CritRevEukaryotGeneExpr.2021037971DOI Listing
February 2022
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