Exploring the SARS-CoV-2 Proteome in the Search of Potential Inhibitors via Structure-Based Pharmacophore Modeling/Docking Approach

To date, SARS-CoV-2 infectious disease, named COVID-19 by the World Health Organization (WHO) in February 2020, has caused millions of infections and hundreds of thousands of deaths. Despite the scientific community efforts, there are currently no approved therapies for treating this coronavirus infection. The process of new drug development is expensive and time-consuming, so that drug repurposing may be the ideal solution to fight the pandemic. In this paper, we selected the proteins encoded by SARS-CoV-2 and using homology modeling we identified the high-quality model of proteins. A structure-based pharmacophore modeling study was performed to identify the pharmacophore features for each target. The pharmacophore models were then used to perform a virtual screening against the DrugBank library (investigational, approved and experimental drugs). Potential inhibitors were identified for each target using XP docking and induced fit docking. MM-GBSA was also performed to better prioritize potential inhibitors. This study will provide new important comprehension of the crucial binding hot spots usable for further studies on COVID-19. Our results can be used to guide supervised virtual screening of large commercially available libraries.

[1]  A. M. Almerico,et al.  Receptor-guided 3D-QSAR approach for the discovery of c-kit tyrosine kinase inhibitors , 2012, Journal of Molecular Modeling.

[2]  P. Kollman,et al.  Use of MM-PBSA in reproducing the binding free energies to HIV-1 RT of TIBO derivatives and predicting the binding mode to HIV-1 RT of efavirenz by docking and MM-PBSA. , 2001, Journal of the American Chemical Society.

[3]  Weida Tong,et al.  In silico drug repositioning: what we need to know. , 2013, Drug discovery today.

[4]  In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication , 2020, Scientific Reports.

[5]  David Schaller,et al.  Next generation 3D pharmacophore modeling , 2020, WIREs Computational Molecular Science.

[6]  Catherine Z. Chen,et al.  Drug Discovery Strategies for SARS-CoV-2 , 2020, The Journal of Pharmacology and Experimental Therapeutics.

[7]  Reaz Uddin,et al.  Identification of chymotrypsin-like protease inhibitors of SARS-CoV-2 via integrated computational approach , 2020, Journal of biomolecular structure & dynamics.

[8]  David I Stuart,et al.  The nsp9 Replicase Protein of SARS-Coronavirus, Structure and Functional Insights , 2004, Structure.

[9]  Marco Tutone,et al.  The In Silico Fischer Lock-and-Key Model: The Combined Use of Molecular Descriptors and Docking Poses for the Repurposing of Old Drugs. , 2020, Methods in molecular biology.

[10]  Anna Maria Almerico,et al.  Conf-VLKA: A structure-based revisitation of the Virtual Lock-and-key Approach. , 2017, Journal of molecular graphics & modelling.

[11]  N. Campillo,et al.  COVID-19: Drug Targets and Potential Treatments , 2020, Journal of medicinal chemistry.

[12]  S. Papapetropoulos,et al.  Drug repurposing from the perspective of pharmaceutical companies , 2018, British journal of pharmacology.

[13]  F. Meyer‐Almes.  Repurposing approved drugs as potential inhibitors of 3CL-protease of SARS-CoV-2: Virtual screening and structure based drug design , 2020, Computational Biology and Chemistry.

[14]  Polina Mamoshina,et al.  Design of efficient computational workflows for in silico drug repurposing. , 2017, Drug discovery today.

[15]  David S. Wishart,et al.  DrugBank: a comprehensive resource for in silico drug discovery and exploration , 2005, Nucleic Acids Res..

[16]  F. Cheng,et al.  Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2 , 2020, Cell Discovery.

[17]  Tingjun Hou,et al.  Molecular dynamics and free energy studies on the wild-type and double mutant HIV-1 protease complexed with amprenavir and two amprenavir-related inhibitors: mechanism for binding and drug resistance. , 2007, Journal of medicinal chemistry.

[18]  Junmei Wang,et al.  Fast Identification of Possible Drug Treatment of Coronavirus Disease-19 (COVID-19) through Computational Drug Repurposing Study , 2020, Journal of chemical information and modeling.

[19]  Zihe Rao,et al.  Crystal Structure of the C-Terminal Cytoplasmic Domain of Non-Structural Protein 4 from Mouse Hepatitis Virus A59 , 2009, PloS one.

[20]  Tudor I. Oprea,et al.  Drug Repurposing: Far Beyond New Targets for Old Drugs , 2012, The AAPS Journal.

[21]  L. Sleire,et al.  Drug repurposing in cancer. , 2017, Pharmacological research.

[22]  Charlotte Harrison,et al.  Coronavirus puts drug repurposing on the fast track , 2020, Nature Biotechnology.

[23]  P E Bourne,et al.  The Protein Data Bank. , 2002, Nucleic acids research.

[24]  Lixia Chen,et al.  Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods , 2020, Acta Pharmaceutica Sinica B.

[25]  Tudor I. Oprea,et al.  Drug Repurposing from an Academic Perspective. , 2011, Drug discovery today. Therapeutic strategies.

[26]  S. Genheden,et al.  The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities , 2015, Expert opinion on drug discovery.

[27]  Gennaro Ciliberto,et al.  Boosting the arsenal against COVID-19 through computational drug repurposing , 2020, Drug Discovery Today.

[28]  Yoonjeong Cha,et al.  Pharma Perspective on Drug Repurposing , 2017 .

[29]  Ola Engkvist,et al.  On the Integration of In Silico Drug Design Methods for Drug Repurposing , 2017, Front. Pharmacol..

[30]  R. Friesner,et al.  Novel procedure for modeling ligand/receptor induced fit effects. , 2006, Journal of medicinal chemistry.

[31]  R. A. Gomes,et al.  Ligand and structure-based virtual screening applied to the SARS-CoV-2 main protease: an in silico repurposing study , 2020, Future medicinal chemistry.

[32]  M. Tutone,et al.  Deciphering the Nonsense Readthrough Mechanism of Action of Ataluren: An in Silico Compared Study. , 2019, ACS medicinal chemistry letters.

[33]  E. Brown,et al.  Drug repurposing for antimicrobial discovery , 2019, Nature Microbiology.

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

[35]  H. Rothan,et al.  The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak , 2020, Journal of Autoimmunity.

[36]  Jacob K. Asiedu,et al.  The Drug Repurposing Hub: a next-generation drug library and information resource , 2017, Nature Medicine.

[37]  Thomas Seidel,et al.  A Computational Approach to Identify Potential Novel Inhibitors against the Coronavirus SARS‐CoV‐2 , 2020, Molecular informatics.

[38]  M. U. Mirza,et al.  Structural elucidation of SARS-CoV-2 vital proteins: Computational methods reveal potential drug candidates against main protease, Nsp12 polymerase and Nsp13 helicase , 2020, Journal of Pharmaceutical Analysis.

[39]  Anna Maria Almerico,et al.  Molecular dynamics studies on Mdm2 complexes: an analysis of the inhibitor influence. , 2012, Biochemical and biophysical research communications.

[40]  Jiahai Zhang,et al.  Repurposing Low-Molecular-Weight Drugs against the Main Protease of Severe Acute Respiratory Syndrome Coronavirus 2 , 2020, The journal of physical chemistry letters.

[41]  A. M. Almerico,et al.  Reverse screening on indicaxanthin from Opuntia ficus-indica as natural chemoactive and chemopreventive agent. , 2018, Journal of theoretical biology.

[42]  Claudio N. Cavasotto,et al.  In silico Drug Repurposing for COVID‐19: Targeting SARS‐CoV‐2 Proteins through Docking and Consensus Ranking , 2020, Molecular informatics.

[43]  Thierry Langer,et al.  A Molecular Dynamics–Shared Pharmacophore Approach to Boost Early‐Enrichment Virtual Screening: A Case Study on Peroxisome Proliferator‐Activated Receptor α , 2017, ChemMedChem.

[44]  Potential inhibitors against papain-like protease of novel coronavirus (SARS-CoV-2) from FDA approved drugs , 2020 .

[45]  M. Tutone,et al.  Multivariate analysis in the identification of biological targets for designed molecular structures: the BIOTA protocol. , 2014, European journal of medicinal chemistry.

[46]  Benjamin J. Polacco,et al.  A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug-Repurposing , 2020, Nature.

[47]  Torsten Schwede,et al.  SWISS-MODEL: homology modelling of protein structures and complexes , 2018, Nucleic Acids Res..

[48]  A. M. Almerico,et al.  Virtual lock-and-key approach: the in silico revival of Fischer model by means of molecular descriptors. , 2011, European journal of medicinal chemistry.

[49]  P. Kollman,et al.  Combined molecular mechanical and continuum solvent approach (MM-PBSA/GBSA) to predict ligand binding , 2000 .