Identifying SARS-CoV-2 Drugs Binding to the Spike Fatty Acid Binding Pocket Using In Silico Docking and Molecular Dynamics

Drugs against novel targets are needed to treat COVID-19 patients, especially as SARS-CoV-2 is capable of rapid mutation. Structure-based de novo drug design and repurposing of drugs and natural products is a rational approach to discovering potentially effective therapies. These in silico simulations can quickly identify existing drugs with known safety profiles that can be repurposed for COVID-19 treatment. Here, we employ the newly identified spike protein free fatty acid binding pocket structure to identify repurposing candidates as potential SARS-CoV-2 therapies. Using a validated docking and molecular dynamics protocol effective at identifying repurposing candidates inhibiting other SARS-CoV-2 molecular targets, this study provides novel insights into the SARS-CoV-2 spike protein and its potential regulation by endogenous hormones and drugs. Some of the predicted repurposing candidates have already been demonstrated experimentally to inhibit SARS-CoV-2 activity, but most of the candidate drugs have yet to be tested for activity against the virus. We also elucidated a rationale for the effects of steroid and sex hormones and some vitamins on SARS-CoV-2 infection and COVID-19 recovery.

[1]  Ashutosh Kumar Singh,et al.  Discovery of anti-SARS-CoV-2 molecules using structure-assisted repurposing approach targeting N-protein , 2023, bioRxiv.

[2]  Clara D. Christ,et al.  Prioritizing Small Sets of Molecules for Synthesis through in‐silico Tools: A Comparison of Common Ranking Methods , 2022, ChemMedChem.

[3]  C. Fernandez-Patron,et al.  Could Endogenous Glucocorticoids Influence SARS-CoV-2 Infectivity? , 2022, Cells.

[4]  Chengyu Jiang,et al.  Potential of angiotensin II receptor blocker telmisartan in reducing mortality among hospitalized patients with COVID-19 compared with recommended drugs , 2022, Cell discovery.

[5]  A. Barabasi,et al.  Identification of potent inhibitors of SARS-CoV-2 infection by combined pharmacological evaluation and cellular network prioritization , 2022, iScience.

[6]  N. Petrovsky,et al.  Potential COVID-19 Therapies from Computational Repurposing of Drugs and Natural Products against the SARS-CoV-2 Helicase , 2022, International journal of molecular sciences.

[7]  J. Glover,et al.  Glucocorticoids Bind to SARS-CoV-2 S1 at Multiple Sites Causing Cooperative Inhibition of SARS-CoV-2 S1 Interaction With ACE2 , 2022, Frontiers in Immunology.

[8]  Mateusz Kciuk,et al.  Discovery of adapalene and dihydrotachysterol as antiviral agents for the Omicron variant of SARS-CoV-2 through computational drug repurposing , 2022, Molecular Diversity.

[9]  Elisabeth L. Moussaud-Lamodière,et al.  Subcellular mapping of the protein landscape of SARS-CoV-2 infected cells for target-centric drug repurposing , 2022, bioRxiv.

[10]  N. Petrovsky,et al.  Computational Repurposing of Drugs and Natural Products Against SARS-CoV-2 Main Protease (Mpro) as Potential COVID-19 Therapies , 2022, Frontiers in Molecular Biosciences.

[11]  C. Schaffitzel,et al.  Synthetic virions reveal fatty acid-coupled adaptive immunogenicity of SARS-CoV-2 spike glycoprotein , 2022, Nature communications.

[12]  W. Dawson,et al.  Drug repurposing for identification of potential spike inhibitors for SARS-CoV-2 using molecular docking and molecular dynamics simulations , 2022, Methods.

[13]  R. Kowsar,et al.  The impact of calcitriol and estradiol on the SARS-CoV-2 biological activity: a molecular modeling approach , 2022, Scientific Reports.

[14]  A. Salonia,et al.  Low testosterone levels predict clinical adverse outcomes in SARS‐CoV‐2 pneumonia patients , 2020, The Journal of Sexual Medicine.

[15]  I. Tsigelny,et al.  Potential SARS-CoV-2 Spike Protein-ACE2 Interface Inhibitors: Repurposing FDA-approved Drugs , 2022, Journal of Exploratory Research in Pharmacology.

[16]  J. Diallo,et al.  Antiviral Potential of the Antimicrobial Drug Atovaquone against SARS-CoV-2 and Emerging Variants of Concern , 2021, ACS infectious diseases.

[17]  J. McKeating,et al.  The circadian clock component BMAL1 regulates SARS-CoV-2 entry and replication in lung epithelial cells , 2021, iScience.

[18]  R. Andino,et al.  Ethacridine inhibits SARS-CoV-2 by inactivating viral particles , 2021, PLoS pathogens.

[19]  S. Mujwar.  Computational repurposing of tamibarotene against triple mutant variant of SARS-CoV-2 , 2021, Computers in Biology and Medicine.

[20]  Y. Sugita,et al.  The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein , 2021, bioRxiv.

[21]  Ankita P. Desai,et al.  Vitamin K & D Deficiencies Are Independently Associated With COVID-19 Disease Severity , 2021, Open forum infectious diseases.

[22]  Oscar A. Negrete,et al.  Discovery of Small-Molecule Inhibitors of SARS-CoV-2 Proteins Using a Computational and Experimental Pipeline , 2021, Frontiers in Molecular Biosciences.

[23]  Tudor I. Oprea,et al.  A critical overview of computational approaches employed for COVID-19 drug discovery , 2021, Chemical Society reviews.

[24]  S. Huo,et al.  Recent advances in developing small-molecule inhibitors against SARS-CoV-2 , 2021, Acta Pharmaceutica Sinica B.

[25]  N. Petrovsky,et al.  In silico comparison of SARS-CoV-2 spike protein-ACE2 binding affinities across species and implications for virus origin , 2021, Scientific Reports.

[26]  F. Pelorosso,et al.  Telmisartan for treatment of Covid-19 patients: An open multicenter randomized clinical trial , 2021, EClinicalMedicine.

[27]  D. Sather,et al.  A Repurposed Drug Screen Identifies Compounds That Inhibit the Binding of the COVID-19 Spike Protein to ACE2 , 2021, Frontiers in Pharmacology.

[28]  M. Sirota,et al.  Transcriptomics-based drug repositioning pipeline identifies therapeutic candidates for COVID-19 , 2021, Scientific Reports.

[29]  D. Sahoo,et al.  Drug repurposing screens identify chemical entities for the development of COVID-19 interventions , 2021, Nature Communications.

[30]  G. Ippolito,et al.  Role of testosterone in SARS-CoV-2 infection: A key pathogenic factor and a biomarker for severe pneumonia , 2021, International Journal of Infectious Diseases.

[31]  R. Dhar,et al.  A large-scale computational screen identifies strong potential inhibitors for disrupting SARS-CoV-2 S-protein and human ACE2 interaction , 2021, Journal of biomolecular structure & dynamics.

[32]  Y. Sakurai,et al.  iPSC screening for drug repurposing identifies anti‐RNA virus agents modulating host cell susceptibility , 2021, FEBS open bio.

[33]  C. Day,et al.  Multidisciplinary Approaches Identify Compounds that Bind to Human ACE2 or SARS-CoV-2 Spike Protein as Candidates to Block SARS-CoV-2–ACE2 Receptor Interactions , 2021, mBio.

[34]  Jonathan E. Schmitz,et al.  Diurnal Variation in SARS-CoV-2 PCR Test Results: Test Accuracy May Vary by Time of Day , 2021, medRxiv.

[35]  A. Marcello,et al.  Combined in silico and in vitro approaches identified the antipsychotic drug lurasidone and the antiviral drug elbasvir as SARS-CoV2 and HCoV-OC43 inhibitors , 2021, Antiviral Research.

[36]  Gengfu Xiao,et al.  Drug Repurposing of Itraconazole and Estradiol Benzoate against COVID‐19 by Blocking SARS‐CoV‐2 Spike Protein‐Mediated Membrane Fusion , 2021, Advanced therapeutics.

[37]  K. Kadler,et al.  Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells , 2021, bioRxiv.

[38]  M. Leboyer,et al.  Chemoinformatic Analysis of Psychotropic and Antihistaminic Drugs in the Light of Experimental Anti-SARS-CoV-2 Activities , 2021, Advances and applications in bioinformatics and chemistry : AABC.

[39]  Charlotte K. Colenso,et al.  Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS‐CoV‐2 Spike Protein** , 2021, Angewandte Chemie.

[40]  Chi‐Huey Wong,et al.  Identification of existing pharmaceuticals and herbal medicines as inhibitors of SARS-CoV-2 infection , 2021, Proceedings of the National Academy of Sciences.

[41]  Jue Wang,et al.  Screened antipsychotic drugs inhibit SARS-CoV-2 binding with ACE2 in vitro , 2020, Life Sciences.

[42]  N. Petrovsky,et al.  Computationally repurposed drugs and natural products against RNA dependent RNA polymerase as potential COVID-19 therapies , 2020, Molecular Biomedicine.

[43]  G. Pinna.  Sex and COVID-19: A Protective Role for Reproductive Steroids , 2020, Trends in Endocrinology & Metabolism.

[44]  A. Goc,et al.  Polyunsaturated ω-3 fatty acids inhibit ACE2-controlled SARS-CoV-2 binding and cellular entry , 2020, Scientific Reports.

[45]  S. Pati,et al.  Drug repurposing for identification of potential inhibitors against SARS-CoV-2 spike receptor-binding domain: An in silico approach , 2020, The Indian journal of medical research.

[46]  A. Marion,et al.  Molecular Modelling Reveals Eight Novel Druggable Binding Sites in SARS-CoV-2’s Spike Protein , 2020 .

[47]  Y. Daali,et al.  The tyrosine kinase inhibitor nilotinib inhibits SARS‐CoV‐2 in vitro , 2020, Basic & clinical pharmacology & toxicology.

[48]  R. Poirier,et al.  High-throughput virtual screening of drug databanks for potential inhibitors of SARS-CoV-2 spike glycoprotein , 2020, Journal of biomolecular structure & dynamics.

[49]  A. Mulholland,et al.  Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein , 2020, Science.

[50]  Christopher M. Horvat,et al.  Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. , 2020, JAMA.

[51]  C. Reynolds,et al.  Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein , 2020, Journal of Computer-Aided Molecular Design.

[52]  P. Manickavasagam.  Spike Protein of SARS-CoV-2: Impact of Single Amino Acid Mutation and Effect of Drug Binding to the Variant-in Silico Analysis , 2020 .

[53]  Krystal L. Matthews,et al.  Broad Anti-coronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo , 2020, Journal of Virology.

[54]  Yong Wang,et al.  Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2 , 2020, Protein & Cell.

[55]  Rafael V. C. Guido,et al.  Discovery of clinically approved drugs capable of inhibiting SARS-CoV-2 in vitro infection using a phenotypic screening strategy and network-analysis to predict their potential to treat covid-19 , 2020, bioRxiv.

[56]  D. Wang,et al.  Calcitriol, the active form of vitamin D, is a promising candidate for COVID-19 prophylaxis , 2020, bioRxiv.

[57]  P. Kar,et al.  An in-silico study on selected organosulfur compounds as potential drugs for SARS-CoV-2 infection via binding multiple drug targets , 2020, Chemical Physics Letters.

[58]  F. Iacovelli,et al.  Targeting the SARS-CoV-2 spike glycoprotein prefusion conformation: virtual screening and molecular dynamics simulations applied to the identification of potential fusion inhibitors , 2020, Virus Research.

[59]  Lee M. Tatham,et al.  Prioritization of Anti‐SARS‐Cov‐2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics , 2020, Clinical pharmacology and therapeutics.

[60]  A. Santucci,et al.  An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors , 2020, Scientific Reports.

[61]  F. Vinckier,et al.  [Repurposing of chlorpromazine in COVID-19 treatment: the reCoVery study]. , 2020, L'Encephale.

[62]  A. Cachia,et al.  Repositionnement de la chlorpromazine dans le traitement du COVID-19 : étude reCoVery , 2020, L'Encéphale.

[63]  S. Ciesek,et al.  Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection , 2020 .

[64]  Lee Smith,et al.  The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality , 2020, Aging Clinical and Experimental Research.

[65]  Xin Zhou,et al.  Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China , 2020, The Journal of Emergency Medicine.

[66]  Andreas Koch,et al.  Comparison of affinity ranking using AutoDock-GPU and MM-GBSA scores for BACE-1 inhibitors in the D3R Grand Challenge 4 , 2019, Journal of Computer-Aided Molecular Design.

[67]  P. Sanseau,et al.  Drug repurposing: progress, challenges and recommendations , 2018, Nature Reviews Drug Discovery.

[68]  Julie Dyall,et al.  Repurposing of Clinically Developed Drugs for Treatment of Middle East Respiratory Syndrome Coronavirus Infection , 2014, Antimicrobial Agents and Chemotherapy.

[69]  Tingjun Hou,et al.  Assessing the Performance of the MM/PBSA and MM/GBSA Methods. 1. The Accuracy of Binding Free Energy Calculations Based on Molecular Dynamics Simulations , 2011, J. Chem. Inf. Model..

[70]  V. Papadopoulos,et al.  Caprospinol: moving from a neuroactive steroid to a neurotropic drug , 2009 .

[71]  Shibo Jiang,et al.  The spike protein of SARS-CoV — a target for vaccine and therapeutic development , 2009, Nature Reviews Microbiology.

[72]  V. Papadopoulos,et al.  Caprospinol: moving from a neuroactive steroid to a neurotropic drug. , 2009, Expert opinion on investigational drugs.

[73]  M. Roden,et al.  Thiazolidinediones Influence Plasma Steroids of Male Obese Zucker Rats. , 2002, Endocrinology.