Publications by authors named "Mubarak A Alamri"

26 Publications

  • Page 1 of 1

Ameliorative Sexual Behavior and Phosphodiesterase-5 Inhibitory Effects of Fruit Extract in Rodents: , , and Study.

J Clin Med 2022 Jun 28;11(13). Epub 2022 Jun 28.

Department of Clinical Pharmacy, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia.

The ethanolic extracts of fruit (SMFE) were evaluated for aphrodisiac activity. The in-vitro phosphodiesterase-5 (PDE-5) inhibition was assessed based on in-silico molecular docking and simulation studies. In addition, the in-vivo sexual behavior was analyzed in the form of mount (MF, ML), intromission (IF, IL), and ejaculation (EF, EL) frequencies and latencies to validate the in-vitro results. Some biochemical parameters, including PDE-5, nitric oxide, and testosterone, were also observed. The above extract constituted β-amyrin, β-sitosterol, and oleanolic acid and showed tremendous binding with phosphodiesterase-5 and sildenafil. Both the sildenafil and ethanolic extracts (200 and 400 mg/kg/d bodyweight) significantly ( < 0.1, < 0.05) increased MF, IF, and EF, respectively. In contrast, ML and IL significantly ( < 0.1) decreased, and EL significantly ( < 0.1) increased compared with a normal group of animals. The ethanolic extracts (200 and 400 mg/kg/d bodyweight) and sildenafil further significantly ( < 0.05, < 0.1) diminished PDE-5 activity significantly ( < 0.05, < 0.1) and enhanced nitric oxide and testosterone levels, as compared with normal rodents. Therefore, the ethanolic extract might be a valuable alternate aphrodisiac for erectile dysfunction.
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http://dx.doi.org/10.3390/jcm11133732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9267661PMC
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

Discovery of Rift Valley fever virus natural pan-inhibitors by targeting its multiple key proteins through computational approaches.

Sci Rep 2022 06 3;12(1):9260. Epub 2022 Jun 3.

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

The Rift Valley fever virus (RVFV) is a zoonotic arbovirus and pathogenic to both humans and animals. Currently, no proven effective RVFV drugs or licensed vaccine are available for human or animal use. Hence, there is an urgent need to develop effective treatment options to control this viral infection. RVFV glycoprotein N (GN), glycoprotein C (GC), and nucleocapsid (N) proteins are attractive antiviral drug targets due to their critical roles in RVFV replication. In present study, an integrated docking-based virtual screening of more than 6000 phytochemicals with known antiviral activities against these conserved RVFV proteins was conducted. The top five hit compounds, calyxin C, calyxin D, calyxin J, gericudranins A, and blepharocalyxin C displayed optimal binding against all three target proteins. Moreover, multiple parameters from the molecular dynamics (MD) simulations and MM/GBSA analysis confirmed the stability of protein-ligand complexes and revealed that these compounds may act as potential pan-inhibitors of RVFV replication. Our computational analyses may contribute toward the development of promising effective drugs against RVFV infection.
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http://dx.doi.org/10.1038/s41598-022-13267-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9163866PMC
June 2022

Anti-Obesity Action of in Rats against High-Fat Diet-Induced Obesity by Blocking the Cannabinoid Receptors.

Plants (Basel) 2022 Apr 25;11(9). Epub 2022 Apr 25.

Department of Clinical Pharmacy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia.

Obesity, type 2 diabetes, and cardiovascular illnesses have known risk factors in the pathophysiology of an unhealthy diet. Obesity now affects almost a third of the world's population and is widely seen as a side effect of the Industrial Revolution. The current study aimed to determine natural phytoconstituents that have a significant role in the management of obesity. In this view, we have selected the plant which has different pharmacological actions and is traditionally used to treat sickness caused by lifestyle modification. The methanolic extract of the plant material was prepared and then further fractionated by means of solvents (n-hexane, chloroform, n-butanol, and water). The absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis was done by taking the active constituent of the plant (Punarnavine, Boeravinone B, and Eupalitin). The molecular docking analysis of these compounds is also performed by targeting the cannabinoid receptor (CR). Structural analysis of the best complex was done using the Discovery Studio visualizer tool. High-performance thin-layer chromatography (HPTLC) analysis was done by using a solvent system (chloroform and methanol in a ratio of 8:2). The study was done on the Sprague-Dawley (SD) rats treated with a high-fat diet to induce obesity and different parameters such as body weight, behavioral activity, organ fat pad weight, lipid profile, and liver biomarkers (AST, ALT, BUN, and creatinine) were estimated. The result of the study suggested that the phytoconstituents of upon molecular docking revealed the possible binding mechanisms with the CR and thus show potent anti-obesity action.
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http://dx.doi.org/10.3390/plants11091158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9105516PMC
April 2022

Thymoquinone Induced Leishmanicidal Effect via Programmed Cell Death in .

ACS Omega 2022 Mar 15;7(12):10718-10728. Epub 2022 Mar 15.

Molecular Virology Laboratory, Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India.

Visceral leishmaniasis (VL) or kala-azar is a vector-borne dreaded protozoal infection that is caused by the parasite . With increases in the dramatic infection rates, present drug toxicity, resistance, and the absence of an approved vaccine, the development of new antileishmanial compounds from plant sources remains the keystone for the control of visceral leishmaniasis. In this study, we evaluated the leishmanicidal effect of thymoquinone against with an and model. Thymoquinone exhibited potent antipromastigote activity with IC and IC concentrations achieved at 6.33 ± 1.21 and 20.71 ± 2.15 μM, respectively, whereas the IC and IC concentrations were found to be 7.83 ± 1.65 and 27.25 ± 2.20 μM against the intramacrophagic form of amastigotes, respectively. Morphological changes in promastigotes and growth reversibility study following treatment confirmed the leishmanicidal effect of thymoquinone. Further, thymoquinone exhibited leishmanicidal activities against promastigote through cytoplasmic shrinkage, membrane blebbing, chromatin condensation, cellular and nuclear shrinkage, and DNA fragmentation, as observed under scanning and transmission electron microscopy analyses. The antileishmanial activity was exerted via programmed cell death as proved by exposure of phosphatidylserine, DNA nicking by TUNEL assay, and loss of mitochondrial membrane potential. Thymoquinone at a concentration of 200 μM was devoid of any cytotoxic effects against mammalian macrophage cells. Thymoquinone showed strong leishmanicidal activity against , which is mediated via an apoptosis mode of parasitic cell death, and accordingly, thymoquinone may be the source of a new lead molecule for the cure of VL.
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http://dx.doi.org/10.1021/acsomega.2c00467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8973115PMC
March 2022

Anti-Diabetic Activity of Bioactive Compound Extracted from Fruit: In-Vitro and Molecular Docking Approaches.

Plants (Basel) 2022 Feb 21;11(4). Epub 2022 Feb 21.

Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia.

is a drupaceous fruit popular for its flavour and health advantages. There is little scientific knowledge about , despite its widespread usage in traditional medicine, in the North-Eastern region of India. Inhibiting the key carbohydrate hydrolysing enzymes is one of the strategies for managing diabetes. Therefore, this study studied the antioxidant and anti-diabetic properties of different fraction fruit extract (SMFFs) from Indian geographical origin by in vitro experimental assays and docking simulation studies. The ADMET prediction for active substances was also investigated using the AdmetSAR database. Based on the binding affinity/molecular interactions between phytocompounds and target enzymes, in silico investigations were done to confirm the in vitro enzymatic inhibitory capability. β-sitosterol in EtOH-F was analysed using RP-HPLC with RP-C18 column as stationary phase and photo diode array detector. The percentage of β-sitosterol was found to be 1.21% ± 0.17% of total weight of extract (). fruit ethanolic extract had a significant inhibitory concentration of 50% against free radicals produced by ABTS (89.71 ± 2.73%) and lipid peroxidation assay (88.26 ± 2.17%) tests. Similarly, the in vitro antidiabetic test findings indicated that inhibited alpha-amylase (73.42 ± 2.01%) and alpha-glucosidase (79.23 ± 1.98%) enzymes dose-dependently. The maximum glycosylated Hb percentage inhibitory activity shown in the ethanolic fraction was (83.97 ± 2.88%) at 500 µg/mL. The glucose uptake of the ethanolic fraction by the yeast cell showed significant ( < 0.05) at 500 µg/mL when compared with metformin (91.37 ± 1.59%), whereas the other fraction did not show the uptake of glucose by the yeast cell at the same concentration. In the docking study, the main phytoconstituents of fruit, such as oleanolic acid, beta-sitosterol, and beta amyrin, show strong affinity for pancreatic α-amylase. These results imply that has α-amylase and α-glucosidase inhibitory properties and may be used as antidiabetic with antioxidant characteristics.
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http://dx.doi.org/10.3390/plants11040562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8880729PMC
February 2022

Novel and Potential Small Molecule Scaffolds as DYRK1A Inhibitors by Integrated Molecular Docking-Based Virtual Screening and Dynamics Simulation Study.

Molecules 2022 Feb 9;27(4). Epub 2022 Feb 9.

Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al Kharj 11942, Saudi Arabia.

The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a novel, promising and emerging biological target for therapeutic intervention in neurodegenerative diseases, especially in Alzheimer's disease (AD). The mol database, comprising rare, diverse and unique compounds, was explored for molecular docking-based virtual screening against the DYRK1A protein, in order to find out potential inhibitors. Ligands exhibiting hydrogen bond interactions with key amino acid residues such as Ile165, Lys188 (catalytic), Glu239 (gk+1), Leu241 (gk+3), Ser242, Asn244, and Asp307, of the target protein, were considered potential ligands. Hydrogen bond interactions with Leu241 (gk+3) were considered key determinants for the selection. High scoring structures were also docked by Glide XP docking in the active sites of twelve DYRK1A related protein kinases, viz. DYRK1B, DYRK2, CDK5/p25, CK1, CLK1, CLK3, GSK3β, MAPK2, MAPK10, PIM1, PKA, and PKCα, in order to find selective DYRK1A inhibitors. MM/GBSA binding free energies of selected ligand-protein complexes were also calculated in order to remove false positive hits. Physicochemical and pharmacokinetic properties of the selected six hit ligands were also computed and related with the proposed limits for orally active CNS drugs. The computational toxicity webserver ProTox-II was used to predict the toxicity profile of selected six hits (mol IDs 9539, 11352, 15938, 19037, 21830 and 21878). The selected six docked ligand-protein systems were exposed to 100 ns molecular dynamics (MD) simulations to validate their mechanism of interactions and stability in the ATP pocket of human DYRK1A kinase. All six ligands were found to be stable in the ATP binding pocket of DYRK1A kinase.
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http://dx.doi.org/10.3390/molecules27041159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8875901PMC
February 2022

Adamantane-derived scaffolds targeting the sigma-2 receptor; an and study.

Saudi Pharm J 2021 Oct 29;29(10):1166-1172. Epub 2021 Aug 29.

Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 16273, Saudi Arabia.

Novel adamantane-based compounds were synthesized and assessed as potential sigma-2 receptor ligands. Molecular docking and 50 ns molecular dynamic simulation were carried out to determine the binding modes, mechanism of interaction, and stability of these compounds within the active site of the sigma-2 receptor. In addition, the ADME-T properties have been explored. The cytotoxicity in cancer cell lines that express sigma-2 receptors was also examined. In addition, the in silico and cytotoxicity data for the new compounds were compared to a reference sigma-2 receptor ligand with high receptor-binding affinity and selectivity. The data suggests that the new compounds interact with the sigma-2 receptor in a comparable manner to the reference compound, and that adamantane can be used as a scaffold to synthesize sigma-2 receptor ligands with useful functional groups that can be used to conjugate moieties for tumor-imaging or cytotoxic cargo delivery.
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http://dx.doi.org/10.1016/j.jsps.2021.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523332PMC
October 2021

Analyzing the effect of mutations in SARS-CoV2 papain-like protease from Saudi isolates on protein structure and drug-protein binding: Molecular modelling and dynamics studies.

Saudi J Biol Sci 2022 Jan 17;29(1):526-533. Epub 2021 Sep 17.

Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia.

The continuous and rapid development of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus remains a health concern especially with the emergence of numerous variants and mutations worldwide. As with other RNA viruses, SARS-CoV-2 has a genetically high mutation rate. These mutations have an impact on the virus characteristics, including transmissibility, antigenicity and development of drug and vaccine resistance. This work was pursued to identify the differences that exist in the papain-like protease (PL) from 58 Saudi isolates in comparison to the first reported sequence from Wuhan, China and determine their implications on protein structure and the inhibitor binding. PL is a key protease enzyme for the host cells invasion and viral proteolytic cleavage, hence, it emerges as a valuable antiviral therapeutic target. Two mutations were identified including D108G and A249V and shown to increase the molecular flexibility of PL protein and alter the protein stability, particularly with D108G mutation. The effect of these mutations on the stability and dynamic behavior of PL structures as well as their effect on the binding of a known inhibitor; GRL0617 were further investigated by molecular docking and dynamic simulation.
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http://dx.doi.org/10.1016/j.sjbs.2021.09.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447498PMC
January 2022

Structural insight into the binding pattern and interaction mechanism of chemotherapeutic agents with Sorcin by docking and molecular dynamic simulation.

Colloids Surf B Biointerfaces 2021 Dec 4;208:112098. Epub 2021 Sep 4.

College of Life Science and Technology, Guangxi University, Nanning, PR China.

Sorcin (SOluble Resistance-related Calcium bInding proteiN) is a calcium binding protein that plays a key role in multidrug resistance (MDR) in human cancers. This study aimed at understanding the binding mechanism and structural basis for the interaction of structurally and functionally unrelated chemotherapeutic agent, namely doxorubicin, etoposide, omacetaxine mepesuccinate and paclitaxel with Sorcin by utilizing docking and molecular dynamic simulation approaches. The docking evaluation of etoposide, omacetaxine mepesuccinate and paclitaxel have shown a high affinity binding with Sorcin at the Ca-binding C-terminal domain (SCBD) in a comparable mode and affinity of binding to doxorubicin. Moreover, all of the docked compounds were shown to interact both hydrophilically and hydrophobically with the same residues within the active pocket which is located at interface of the Sorcin and collectively formed by EF5 loop, G helix and EF4 loop. However, the MD simulations revealed that the dynamics of Sorcin structure is different in the presence of the compounds when compared and contrasted to the Apo Sorcin, particularly in the first 25 ns, after which each system gained considerable structure stability. The difference in dynamics might be the outcome of high N and C-terminal flexibility that seem not to disturb compounds binding conformation but more likely is affecting chemical interaction network by breaking and establishing old and new hydrogen bonds, respectively. This detailed mechanistic understanding of different chemotherapeutic agents binding to Sorcin might be useful to open windows for designing and developing new inhibitors that are potentially capable of reversing the MDR in human cancers.
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http://dx.doi.org/10.1016/j.colsurfb.2021.112098DOI Listing
December 2021

Synthesis, Anticancer Screening of Some Novel Trimethoxy Quinazolines and VEGFR2, EGFR Tyrosine Kinase Inhibitors Assay; Molecular Docking Studies.

Molecules 2021 May 18;26(10). Epub 2021 May 18.

Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam bin Abdulaziz University, Alkharj 11942, Saudi Arabia.

A new series of 8-methoxy-2-trimethoxyphenyl-3-substituted quinazoline-4(3)-one compounds were designed, synthesized, and screened for antitumor activity against three cell lines, namely, Hela, A549, and MDA compared to docetaxel as reference drug. The molecular docking was performed using Autodock Vina program and 20 ns molecular dynamics (MD) simulation was performed using GROMACS 2018.1 software. Compound 6 was the most potent antitumor of the new synthesized compounds and was evaluated as a VEGFR2 and EGFR inhibitor with (IC50, 98.1 and 106 nM respectively) compared to docetaxel (IC50, 89.3 and 56.1 nM respectively). Compounds 2, 6, 10, and 8 showed strong cytotoxic activities against the Hela cell line with IC50 of, 2.13, 2.8, 3.98, and 4.94 µM, respectively, relative to docetaxel (IC50, 9.65 µM). Compound 11 showed strong cytotoxic activity against A549 cell line (IC50, 4.03 µM) relative to docetaxel (IC50, 10.8 µM). Whereas compounds 6 and 9 showed strong cytotoxic activity against MDA cell line (IC50, 0.79, 3.42 µM, respectively) as compared to docetaxel (IC50, 3.98 µM).
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http://dx.doi.org/10.3390/molecules26102992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157871PMC
May 2021

Inhibition of Chikungunya Virus Infection by 4-Hydroxy-1-Methyl-3-(3-morpholinopropanoyl)quinoline-2(1)-one (QVIR) Targeting nsP2 and E2 Proteins.

ACS Omega 2021 Apr 31;6(14):9791-9803. Epub 2021 Mar 31.

Molecular Virology Laboratory, Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India.

The re-emergence of Chikungunya virus (CHIKV) infection in humans with no approved antiviral therapies or vaccines is one of the major problems with global significance. In the present investigation, we screened 80 in-house quinoline derivatives for their anti-CHIKV activity by computational techniques and found 4-hydroxy-1-methyl-3-(3-morpholinopropanoyl)quinoline-2(1)-one (QVIR) to have potential binding affinities with CHIKV nsP2 and E2 glycoproteins. QVIR was evaluated for its anti-CHIKV potential. QVIR showed strong inhibition of CHIKV infection with an EC (50% effective concentration) value of 2.2 ± 0.49 μM without significant cytotoxicity (CC > 200 μM) and was chosen for further elucidation of its antiviral mechanism. The infectious viral particle formation was abolished by approximately 72% at a QVIR concentration of 20 μM during infection in the BHK-21 cell line, and the CHIKV RNA synthesis was diminished by 84% for nsP2 as well as 74% for E2, whereas the levels of viral proteins were decreased by 69.9% for nsP2 and 53.9% for E2. Flow cytometry analysis confirmed a huge decline in the expression of viral nsP2 and E2 proteins by 71.84 and 67.7%, respectively. Time of addition experiments indicated that QVIR inhibited viral infection at early and late stages of viral replication cycle, and the optimal inhibition was observed at 16 h post infection. The present study advocates for the first time that QVIR acts as a substantial and potent inhibitor against CHIKV and might be as an auspicious novel drug candidate for the development of therapeutic agents against CHIKV infections.
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http://dx.doi.org/10.1021/acsomega.1c00447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047676PMC
April 2021

Discovery of anti-MERS-CoV small covalent inhibitors through pharmacophore modeling, covalent docking and molecular dynamics simulation.

J Mol Liq 2021 May 20;330:115699. Epub 2021 Feb 20.

Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.

Middle east respiratory syndrome coronavirus (MERS-CoV) is a fatal pathogen that poses a serious health risk worldwide and especially in the middle east countries. Targeting the MERS-CoV 3-chymotrypsin-like cysteine protease (3CL) with small covalent inhibitors is a significant approach to inhibit replication of the virus. The present work includes generating a pharmacophore model based on the X-ray crystal structures of MERS-CoV 3CL in complex with two covalently bound inhibitors. In silico screening of covalent chemical database having 31,642 compounds led to the identification of 378 compounds that fulfils the pharmacophore queries. Lipinski rules of five were then applied to select only compounds with the best physiochemical properties for orally bioavailable drugs. 260 compounds were obtained and subjected to covalent docking-based virtual screening to determine their binding energy scores. The top three candidate compounds, which were shown to adapt similar binding modes as the reported covalent ligands were selected. The mechanism and stability of binding of these compounds were confirmed by 100 ns molecular dynamic simulation followed by MM/PBSA binding free energy calculation. The identified compounds can facilitate the rational design of novel covalent inhibitors of MERS-CoV 3CL enzyme as anti-MERS CoV drugs.
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http://dx.doi.org/10.1016/j.molliq.2021.115699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040153PMC
May 2021

Synthesis, characterization, biological evaluation and molecular docking of a new quinazolinone-based derivative as a potent dual inhibitor for VEGFR-2 and EGFR tyrosine kinases.

J Biomol Struct Dyn 2021 Mar 8:1-7. Epub 2021 Mar 8.

Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia.

An efficient process for the preparation of a new ethyl 2-((3-(4-fluorophenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)thio) acetate () was described. The prepared derivative was synthesized using the S-arylation method. Several analytical techniques, such as NMR, Raman and infrared spectroscopy, were used to characterize this compound. The compound was screened for cytotoxic activity against three human cancer cell lines: human cervical cancer (HeLa), human lung adenocarcinoma (A549) and triple negative breast cancer (MDA-MB-231) cells using an MTT assay. It exhibited potent cytotoxic activity against the tested cell lines with IC values in the low micromolar range when compared to a standard drug, docetaxel. It also displayed potent inhibitory activity towards VEGFR-2 and EGFR tyrosine kinases, reflecting its potential to act as an effective anti-cancer agent.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2021.1890221DOI Listing
March 2021

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches.

J Pharm Anal 2020 Dec 28;10(6):546-559. Epub 2020 Aug 28.

College of Life Science and Technology, Guangxi University, Nanning, China.

The papain-like protease (PL) is vital for the replication of coronaviruses (CoVs), as well as for escaping innate-immune responses of the host. Hence, it has emerged as an attractive antiviral drug-target. In this study, computational approaches were employed, mainly the structure-based virtual screening coupled with all-atom molecular dynamics (MD) simulations to computationally identify specific inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PL, which can be further developed as potential pan-PL based broad-spectrum antiviral drugs. The sequence, structure, and functional conserveness of most deadly human CoVs PL were explored, and it was revealed that functionally important catalytic triad residues are well conserved among SARS-CoV, SARS-CoV-2, and middle east respiratory syndrome coronavirus (MERS-CoV). The subsequent screening of a focused protease inhibitors database composed of ∼7,000 compounds resulted in the identification of three candidate compounds, ADM_13083841, LMG_15521745, and SYN_15517940. These three compounds established conserved interactions which were further explored through MD simulations, free energy calculations, and residual energy contribution estimated by MM-PB(GB)SA method. All these compounds showed stable conformation and interacted well with the active residues of SARS-CoV-2 PL, and showed consistent interaction profile with SARS-CoV PL and MERS-CoV PL as well. Conclusively, the reported SARS-CoV-2 PL specific compounds could serve as seeds for developing potent pan-PL based broad-spectrum antiviral drugs against deadly human coronaviruses. Moreover, the presented information related to binding site residual energy contribution could lead to further optimization of these compounds.
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http://dx.doi.org/10.1016/j.jpha.2020.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453225PMC
December 2020

Structure-based virtual screening and molecular dynamics of phytochemicals derived from Saudi medicinal plants to identify potential COVID-19 therapeutics.

Arab J Chem 2020 Sep 9;13(9):7224-7234. Epub 2020 Aug 9.

Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia.

Coronavirus disease 2019 (COVID-19) has affected almost every country in the world by causing a global pandemic with a high mortality rate. Lack of an effective vaccine and/or antiviral drugs against SARS-CoV-2, the causative agent, has severely hampered the response to this novel coronavirus. Natural products have long been used in traditional medicines to treat various diseases, and purified phytochemicals from medicinal plants provide a valuable scaffold for the discovery of new drug leads. In the present study, we performed a computational screening of an in-house database composed of ~1000 phytochemicals derived from traditional Saudi medicinal plants with recognised antiviral activity. Structure-based virtual screening was carried out against three druggable SARS-CoV-2 targets, viral RNA-dependent RNA polymerase (RdRp), 3-chymotrypsin-like cysteine protease (3CL) and papain like protease (PL) to identify putative inhibitors that could facilitate the development of potential anti-COVID-19 drug candidates. Computational analyses identified three compounds inhibiting each target, with binding affinity scores ranging from -9.9 to -6.5 kcal/mol. Among these, luteolin 7-rutinoside, chrysophanol 8-(6-galloylglucoside) and kaempferol 7-(6″-galloylglucoside) bound efficiently to RdRp, while chrysophanol 8-(6-galloylglucoside), 3,4,5-tri-O-galloylquinic acid and mulberrofuran G interacted strongly with 3CL, and withanolide A, isocodonocarpine and calonysterone bound tightly to PL. These potential drug candidates will be subjected to further in vitro and in vivo studies and may assist the development of effective anti-COVID-19 drugs.
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http://dx.doi.org/10.1016/j.arabjc.2020.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415226PMC
September 2020

Structure Prediction of SPAK C-terminal Domain and Analysis of its Binding to RFXV/I Motifs by Homology Modelling, Docking and Molecular Dynamics Simulation Studies.

Curr Comput Aided Drug Des 2021 ;17(5):666-675

Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj- 11942, Saudi Arabia.

Background: The STE20/SPS1-related proline/alanine-rich kinase (SPAK) is a component of WNK-SPAK/OSR1 signaling pathway that plays an essential role in blood pressure regulation. The function of SPAK is mediated by its highly conserved C-terminal domain (CTD) that interacts with RFXV/I motifs of upstream activators, WNK kinases, and downstream substrate, cation- chloride cotransporters.

Objective: To determine and validate the three-dimensional structure of the CTD of SPAK and to study and analyze its interaction with the RFXV/I motifs.

Methods: A homology model of SPAK CTD was generated and validated through multiple approaches. The model was based on utilizing the OSR1 protein kinase as a template. This model was subjected to a 100 ns molecular dynamic (MD) simulation to evaluate its dynamic stability. The final equilibrated model was used to dock the RFQV-peptide derived from WNK4 into the primary pocket that was determined based on the homology sequence between human SPAK and OSR1 CTDs. The mechanism of interaction, conformational rearrangement and dynamic stability of the binding of RFQV-peptide to SPAK CTD were characterized by molecular docking and molecular dynamic simulation.

Results: The MD simulation suggested that the binding of RFQV induces a large conformational change due to the distribution of salt bridge within the loop regions. These results may help in understanding the relationship between the structure and function of SPAK CTD and to support the drug design of potential SPAK kinase inhibitors as antihypertensive agents.

Conclusion: This study provides deep insight into the SPAK CTD structure and function relationship.
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http://dx.doi.org/10.2174/1573409916666200712140941DOI Listing
January 2022

Pharmacoinformatics and molecular dynamics simulation studies reveal potential covalent and FDA-approved inhibitors of SARS-CoV-2 main protease 3CL.

J Biomol Struct Dyn 2021 08 24;39(13):4936-4948. Epub 2020 Jun 24.

Structural Bioinformatics Laboratory, Faculty of Science and Engineering, Biochemistry, Åbo Akademi University, Turku, Finland.

The SARS-CoV-2 was confirmed to cause the global pandemic of coronavirus disease 2019 (COVID-19). The 3-chymotrypsin-like protease (3CLpro), an essential enzyme for viral replication, is a valid target to combat SARS-CoV and MERS-CoV. In this work, we present a structure-based study to identify potential covalent inhibitors containing a variety of chemical warheads. The targeted Asinex Focused Covalent (AFCL) library was screened based on different reaction types and potential covalent inhibitors were identified. In addition, we screened FDA-approved protease inhibitors to find candidates to be repurposed against SARS-CoV-2 3CLpro. A number of compounds with significant covalent docking scores were identified. These compounds were able to establish a covalent bond (C-S) with the reactive thiol group of Cys145 and to form favorable interactions with residues lining the substrate-binding site. Moreover, paritaprevir and simeprevir from FDA-approved protease inhibitors were identified as potential inhibitors of SARS-CoV-2 3CLpro. The mechanism and dynamic stability of binding between the identified compounds and SARS-CoV-2 3CLpro were characterized by molecular dynamics (MD) simulations. The identified compounds are potential inhibitors worthy of further development as COVID-19 drugs. Importantly, the identified FDA-approved anti-hepatitis-C virus (HCV) drugs paritaprevir and simeprevir could be ready for clinical trials to treat infected patients and help curb COVID-19. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1782768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332866PMC
August 2021

Structural basis of SARS-CoV-2 3CL and anti-COVID-19 drug discovery from medicinal plants.

J Pharm Anal 2020 Aug 26;10(4):313-319. Epub 2020 Mar 26.

College of Life Science and Technology, Guangxi University, Nanning, 530004, PR China.

The recent pandemic of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has raised global health concerns. The viral 3-chymotrypsin-like cysteine protease (3CL) enzyme controls coronavirus replication and is essential for its life cycle. 3CL is a proven drug discovery target in the case of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Recent studies revealed that the genome sequence of SARS-CoV-2 is very similar to that of SARS-CoV. Therefore, herein, we analysed the 3CL sequence, constructed its 3D homology model, and screened it against a medicinal plant library containing 32,297 potential anti-viral phytochemicals/traditional Chinese medicinal compounds. Our analyses revealed that the top nine hits might serve as potential anti- SARS-CoV-2 lead molecules for further optimisation and drug development process to combat COVID-19.
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http://dx.doi.org/10.1016/j.jpha.2020.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156227PMC
August 2020

Pharmacophore and docking-based sequential virtual screening for the identification of novel Sigma 1 receptor ligands.

Bioinformation 2019 10;15(8):586-595. Epub 2019 Sep 10.

Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia.

Sigma 1 receptor (σ1), a small transmembrane protein expressed in most human cells participates in modulating the function of other membrane proteins such as G protein coupled receptors and ion channels. Several ligands targeting this receptor are currently in clinical trials for the treatment of Alzheimer's disease, ischemic stroke and neuro-pathic pain. Hence, this receptor has emerged as an attractive target for the treatment of neuro-pathological diseases with unmet medical needs. It is of interest to identify and characterise novelσ1 receptor ligands with different chemical scaffolds using computer-aided drug designing approach. In this work, a GPCR-focused chemical library consisting of 8543 compounds was screened by pharmacophore and docking-based virtual screening methods using LigandScout 4.3 and Autodock Vina 1.1.2 in PyRx 0.8, respectively. The pharmacophore model was constructed based on the interactions of a selective agonist and another antagonist ligand with high binding affinity to the human σ1receptors. Candidate compounds were filtered sequentially by pharmacophore-fit scores, docking energy scores, drug-likeness filters and ADMET properties. The binding mode and pharmacophore mapping of candidate compounds were analysed by Autodock Vina 1.1.2 and LigandScout 4.3 programs, respectively. A pharmacophore model composed of three hydrophobic and positive ionizable features with recognized geometry was built and used as a 3D query for screening a GPCR-focused chemical library by LigandScout 4.3 program. Among the screened 8543 compounds, 159 candidate compounds were obtained from pharmacophore-based screening. 45 compounds among them bound to σ 1receptor with high binding-affinity scores in comparison to the co-crystallized ligand. Amongst these, top five candidate compounds with excellent druglikeness and ADMET properties were selected. These five candidate compounds may act as potential σ1 receptor ligands.
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http://dx.doi.org/10.6026/97320630015586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822515PMC
September 2019

Sequence specific assignment and determination of OSR1 C-terminal domain structure by NMR.

Biochem Biophys Res Commun 2019 04 17;512(2):338-343. Epub 2019 Mar 17.

Cardiff School of Pharmacy and Pharmaceutical Sciences, King Edward VII Avenue, Cardiff University, Cardiff, CF10 3NB, UK. Electronic address:

The binding of SPAK and OSR1 kinases to their upstream WNK kinases is mediated by the interaction of their highly conserved SPAK and OSR1 C-terminal domain (CTD) to RFx [V/I] peptide sequences from WNK kinases. A SPAK CTD knock-in mouse, where SPAK was unable to bind WNK kinases, exhibited low blood pressure. This highlighted the inhibition of SPAK and OSR1 kinases binding to their upstream WNK kinases as a plausible strategy in the discovery of new antihypertensive agents. To facilitate such endeavour, we herein report the optimisation and expression of isotopically labelled OSR1 CTD in E.coli and a structural model based on the sequence specific NMR assignments giving insights into the structure of apo OSR1 CTD. Additionally, we identified the OSR1 CTD amino acid residues that are important for the binding of an 18-mer RFQV peptide derived from human WNK4. Collectively, the NMR backbone assignments and the generated OSR1 CTD 3D model reported in this work will be a powerful resource for the NMR-based discovery of small molecule OSR1 (and SPAK) kinase inhibitors as potential antihypertensive agents.
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http://dx.doi.org/10.1016/j.bbrc.2019.03.065DOI Listing
April 2019

C-terminal phosphorylation of SPAK and OSR1 kinases promotes their binding and activation by the scaffolding protein MO25.

Biochem Biophys Res Commun 2018 09 27;503(3):1868-1873. Epub 2018 Jul 27.

School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.

SPAK and OSR1 are two protein kinases that play important roles in regulating the function of numerous ion co-transporters. They are activated by two distinct mechanisms that involve initial phosphorylation at their T-loops by WNK kinases and subsequent binding to a scaffolding protein termed MO25. To understand this latter SPAK and OSR1 regulation mechanism, we herein show that MO25 binding to these two kinases is enhanced by serine phosphorylation in their highly conserved WEWS motif, which is located in their C-terminal domains. Furthermore, we show that this C-terminal phosphorylation is carried out by WNK kinases in vitro and involves WNK kinases in cells. Mutagenesis studies revealed key MO25 residues that are important for MO25 binding and activation of SPAK and OSR1 kinases. Collectively, this study provides new insights into the MO25-mediated activation of SPAK and OSR1 kinases, which are emerging as important players in regulating ion homeostasis.
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http://dx.doi.org/10.1016/j.bbrc.2018.07.128DOI Listing
September 2018

The Photosensitising Clinical Agent Verteporfin Is an Inhibitor of SPAK and OSR1 Kinases.

Chembiochem 2018 10 22;19(19):2072-2080. Epub 2018 Aug 22.

School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK.

STE20/SPS1-related proline/alanine-rich kinase (SPAK) and oxidative-stress-responsive kinase 1 (OSR1) are two serine/threonine protein kinases that play key roles in regulating ion homeostasis. Various SPAK and OSR1 mouse models exhibited reduced blood pressure. Herein, the discovery of verteporfin, a photosensitising agent used in photodynamic therapy, as a potent inhibitor of SPAK and OSR1 kinases is reported. It is shown that verteporfin binds the kinase domains of SPAK and OSR1 and inhibits their catalytic activity in an adenosine triphosphate (ATP)-independent manner. In cells, verteporfin was able to suppress the phosphorylation of the ion co-transporter NKCC1; a downstream physiological substrate of SPAK and OSR1 kinases. Kinase panel screening indicated that verteporfin inhibited a further eight protein kinases more potently than that of SPAK and OSR1. Although verteporfin has largely been studied as a modifier of the Hippo signalling pathway, this work indicates that the WNK-SPAK/OSR1 signalling cascade is also a target of this clinical agent. This finding could explain the fluctuation in blood pressure noted in patients and animals treated with this drug.
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http://dx.doi.org/10.1002/cbic.201800272DOI Listing
October 2018

WNK Signaling Inhibitors as Potential Antihypertensive Drugs.

ChemMedChem 2017 10 26;12(20):1677-1686. Epub 2017 Sep 26.

School of Pharmacy and Pharmaceutical Sciences, College of Biomedical and Life Sciences, Cardiff University, Cardiff, CF10 3NB, UK.

Since the discovery of WNK mutations that cause an inherited form of hypertension in humans, there has been increasing interest in targeting WNK signaling as a novel strategy for modulating blood pressure. This notion is now supported by numerous mouse models with impaired WNK signaling that exhibit reduced blood pressure. Biochemical analyses of the various protein components that make up this signaling pathway have identified a number of plausible molecular targets that are amenable to targeting by small molecules. To date, a selection of small-molecule WNK signaling inhibitors have been identified and have shown promise in suppressing the activity of WNK signaling in cells and in animals. In this Minireview, we briefly discuss the WNK signaling pathway and provide an overview of the various druggable targets within this cascade, as well as the different WNK signaling inhibitors discovered to date.
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http://dx.doi.org/10.1002/cmdc.201700425DOI Listing
October 2017

Rafoxanide and Closantel Inhibit SPAK and OSR1 Kinases by Binding to a Highly Conserved Allosteric Site on Their C-terminal Domains.

ChemMedChem 2017 05 12;12(9):639-645. Epub 2017 Apr 12.

School of Pharmacy and Pharmaceutical Sciences, Redwood Building, Cardiff University, Cardiff, CF10 3NB, UK.

SPAK and OSR1 are two protein kinases that have emerged as attractive targets in the discovery of novel antihypertensive agents due to their role in regulating electrolyte balance in vivo. Herein we report the identification of an allosteric pocket on the highly conserved C-terminal domains of these two kinases, which influences their activity. We also show that some known WNK signaling inhibitors bind to this allosteric site. Using in silico screening, we identified the antiparasitic agent rafoxanide as a novel allosteric inhibitor of SPAK and OSR1. Collectively, this work will facilitate the rational design of novel SPAK and OSR1 kinase inhibitors that could be useful antihypertensive agents.
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http://dx.doi.org/10.1002/cmdc.201700077DOI Listing
May 2017

Towards the Development of Small-Molecule MO25 Binders as Potential Indirect SPAK/OSR1 Kinase Inhibitors.

Chembiochem 2017 03 30;18(5):460-465. Epub 2017 Jan 30.

School of Pharmacy, University of Birmingham, Edgbaston Park Road, Birmingham, B15 2TT, UK.

The binding of the scaffolding protein MO25 to SPAK and OSR1 protein kinases, which regulate ion homeostasis, causes increases of up to 100-fold in their catalytic activity. Various animal models have shown that the inhibition of SPAK and OSR1 lowers blood pressure, and so here we present a new indirect approach to inhibiting SPAK and OSR1 kinases by targeting their protein partner MO25. To explore this approach, we developed a fluorescent polarisation assay and used it in screening of a small in-house library of ≈4000 compounds. This led to the identification of one compound-HK01-as the first small-molecule inhibitor of the MO25-dependent activation of SPAK and OSR1 in vitro. Our data confirm the feasibility of targeting this protein-protein interaction by small-molecule compounds and highlights their potential to modulate ion co-transporters and thus cellular electrolyte balance.
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http://dx.doi.org/10.1002/cbic.201600620DOI Listing
March 2017
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