Exploration of natural compounds with anti-SARS-CoV-2 activity via inhibition of SARS-CoV-2 Mpro

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a dreaded pandemic in lack of specific therapeutic agent. SARS-CoV-2 Mpro, an essential factor in viral pathogenesis, is recognized as a prospective therapeutic target in drug discovery against SARS-CoV-2. To tackle this pandemic, Food and Drug Administration-approved drugs are being screened against SARS-CoV-2 Mpro via in silico and in vitro methods to detect the best conceivable drug candidates. However, identification of natural compounds with anti-SARS-CoV-2 Mpro potential have been recommended as rapid and effective alternative for anti-SARS-CoV-2 therapeutic development. Thereof, a total of 653 natural compounds were identified against SARS-CoV-2 Mpro from NP-lib database at MTi-OpenScreen webserver using virtual screening approach. Subsequently, top four potential compounds, i.e. 2,3-Dihydroamentoflavone (ZINC000043552589), Podocarpusflavon-B (ZINC000003594862), Rutin (ZINC000003947429) and Quercimeritrin 6"-O-L-arabinopyranoside (ZINC000070691536), and co-crystallized N3 inhibitor as reference ligand were considered for stringent molecular docking after geometry optimization by DFT method. Each compound exhibited substantial docking energy >-12 kcal/mol and molecular contacts with essential residues, including catalytic dyad (His41 and Cys145) and substrate binding residues, in the active pocket of SARS-CoV-2 Mpro against N3 inhibitor. The screened compounds were further scrutinized via absorption, distribution, metabolism, and excretion - toxicity (ADMET), quantum chemical calculations, combinatorial molecular simulations and hybrid QM/MM approaches. Convincingly, collected results support the potent compounds for druglikeness and strong binding affinity with the catalytic pocket of SARS-CoV-2 Mpro. Hence, selected compounds are advocated as potential inhibitors of SARS-CoV-2 Mpro and can be utilized in drug development against SARS-CoV-2 infection.

[1]  K. Morokuma,et al.  A NEW ONIOM IMPLEMENTATION IN GAUSSIAN98. PART I. THE CALCULATION OF ENERGIES, GRADIENTS, VIBRATIONAL FREQUENCIES AND ELECTRIC FIELD DERIVATIVES , 1999 .

[2]  Donald G Truhlar,et al.  Density functionals with broad applicability in chemistry. , 2008, Accounts of chemical research.

[3]  Integrating molecular probes and molecular dynamics to reveal binding modes of GLUT5 activatory and inhibitory ligands. , 2018, Chemical communications.

[4]  Jérôme Hert,et al.  Learning Medicinal Chemistry Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Rules from Cross-Company Matched Molecular Pairs Analysis (MMPA). , 2017, Journal of medicinal chemistry.

[5]  Ricardo Macarron,et al.  Critical review of the role of HTS in drug discovery. , 2006, Drug discovery today.

[6]  Z. Bian,et al.  Bioactive natural compounds against human coronaviruses: a review and perspective , 2020, Acta Pharmaceutica Sinica B.

[7]  Parr,et al.  Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. , 1988, Physical review. B, Condensed matter.

[8]  S. Kang,et al.  From SARS to SARS-CoV-2, insights on structure, pathogenicity and immunity aspects of pandemic human coronaviruses , 2020, Infection, Genetics and Evolution.

[9]  W. Förner,et al.  Correlated ab initio and density functional calculations on small model molecules for the unit cell of polyparaphenylene in its aromatic and quinoidal forms: equilibrium geometries and vibrational spectra , 2002 .

[10]  M. Karabacak,et al.  The spectroscopic (FT-Raman, FT-IR, UV and NMR), molecular electrostatic potential, polarizability and hyperpolarizability, NBO and HOMO-LUMO analysis of monomeric and dimeric structures of 4-chloro-3,5-dinitrobenzoic acid. , 2012, Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy.

[11]  C. Lipinski.  Lead- and drug-like compounds: the rule-of-five revolution. , 2004, Drug discovery today. Technologies.

[12]  A. Hajipour,et al.  Protein–ligand interaction study of signal transducer smoothened protein with different drugs: molecular docking and QM/MM calculations , 2015 .

[13]  Arthur J. Olson,et al.  AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading , 2009, J. Comput. Chem..

[14]  R. Hilgenfeld,et al.  Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors , 2020, Science.

[15]  S. Bharadwaj,et al.  Structure-based screening and validation of bioactive compounds as Zika virus methyltransferase (MTase) inhibitors through first-principle density functional theory, classical molecular simulation and QM/MM affinity estimation , 2020, Journal of biomolecular structure & dynamics.

[16]  Dongqing Wei,et al.  Deciphering G-Protein-Coupled Receptor 119 Agonists as Promising Strategy against Type 2 Diabetes Using Systems Biology Approach , 2018, ACS Omega.

[17]  S. Grimme,et al.  Why the standard B3LYP/6-31G* model chemistry should not be used in DFT calculations of molecular thermochemistry: understanding and correcting the problem. , 2012, The Journal of organic chemistry.

[18]  John L. Klepeis,et al.  Molecular dynamics - Scalable algorithms for molecular dynamics simulations on commodity clusters , 2006, SC.

[19]  Pierre Tufféry,et al.  MTiOpenScreen: a web server for structure-based virtual screening , 2015, Nucleic Acids Res..

[20]  Alimuddin Zumla,et al.  Coronaviruses — drug discovery and therapeutic options , 2016, Nature Reviews Drug Discovery.

[21]  Junmei Wang,et al.  End-Point Binding Free Energy Calculation with MM/PBSA and MM/GBSA: Strategies and Applications in Drug Design. , 2019, Chemical reviews.

[22]  K. D. Silva,et al.  Non-linear optical properties of novel fluorenyl derivatives—ab initio quantum chemical calculations , 2002 .

[23]  Victor M Corman,et al.  Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR , 2020, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[24]  J. Calixto,et al.  The role of natural products in modern drug discovery. , 2019, Anais da Academia Brasileira de Ciencias.

[25]  S. Perlman,et al.  Coronaviruses post-SARS: update on replication and pathogenesis , 2009, Nature Reviews Microbiology.

[26]  Zhènglì Shí,et al.  Origin and evolution of pathogenic coronaviruses , 2018, Nature Reviews Microbiology.

[27]  B. Canard,et al.  Structure-Activity Relationship Study of Biflavonoids on the Dengue Virus Polymerase DENV-NS5 RdRp , 2013, Planta Medica.

[28]  Hermann Stoll,et al.  Results obtained with the correlation energy density functionals of becke and Lee, Yang and Parr , 1989 .

[29]  M. Jayaweera,et al.  Transmission of COVID-19 virus by droplets and aerosols: A critical review on the unresolved dichotomy , 2020, Environmental Research.

[30]  Jans H. Alzate-Morales,et al.  Performance of the MM/GBSA scoring using a binding site hydrogen bond network-based frame selection: the protein kinase case. , 2014, Physical chemistry chemical physics : PCCP.

[31]  New Dihydrobiflavones from the Moss Plagiomnium cuspidatum , 1989 .

[32]  A. A. Siddiqui,et al.  Role of Natural Products in Drug Discovery Process , 2014 .

[33]  P. Wutzler,et al.  Inhibition of fatty acid synthase by amentoflavone reduces coxsackievirus B3 replication , 2011, Archives of Virology.

[34]  J. Sharifi‐Rad,et al.  A Perspective on Emerging Therapeutic Interventions for COVID-19 , 2020, Frontiers in Public Health.

[35]  Leo S. D. Caves,et al.  Bio3d: An R Package , 2022 .

[36]  Strohl,et al.  The role of natural products in a modern drug discovery program. , 2000, Drug discovery today.

[37]  R. Pearson.  Electronic spectra and chemical reactivity , 1988 .

[38]  Conrad C. Huang,et al.  UCSF Chimera—A visualization system for exploratory research and analysis , 2004, J. Comput. Chem..

[39]  S. Kang,et al.  Discovery of Ganoderma lucidum triterpenoids as potential inhibitors against Dengue virus NS2B-NS3 protease , 2019, Scientific Reports.

[40]  W. Kohn,et al.  Self-Consistent Equations Including Exchange and Correlation Effects , 1965 .

[41]  J. Beutler,et al.  Natural Products as a Foundation for Drug Discovery , 2009, Current protocols in pharmacology.

[42]  Y. Hayashi,et al.  An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy , 2016, Journal of medicinal chemistry.

[43]  Sang Gu Kang,et al.  Computational insights into tetracyclines as inhibitors against SARS-CoV-2 Mpro via combinatorial molecular simulation calculations , 2020, Life Sciences.

[44]  Rajesh Kumar,et al.  DenvInD: dengue virus inhibitors database for clinical and molecular research , 2020, Briefings Bioinform..

[45]  Walter Thiel,et al.  QM/MM methods for biomolecular systems. , 2009, Angewandte Chemie.

[46]  A. Toit.  Outbreak of a novel coronavirus , 2020 .

[47]  R F Schinazi,et al.  In vitro anti-HIV activity of biflavonoids isolated from Rhus succedanea and Garcinia multiflora. , 1997, Journal of natural products.

[48]  Petra Schneider,et al.  Counting on natural products for drug design. , 2016, Nature chemistry.

[49]  H. Farrokhpour,et al.  Design of novel potential aromatase inhibitors via hybrid pharmacophore approach: docking improvement using the QM/MM method , 2015 .

[50]  A comparison of crystallographic and DFT optimized geometries on two taxane diterpenoids and docking studies with phospholipase A2 , 2012, Medicinal Chemistry Research.

[51]  Hualiang Jiang,et al.  Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors , 2020, Nature.

[52]  Arieh Warshel,et al.  On possible pitfalls in ab initio quantum mechanics/molecular mechanics minimization approaches for studies of enzymatic reactions. , 2005, The journal of physical chemistry. B.

[53]  E. Holmes,et al.  Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding , 2020, The Lancet.

[54]  Z. Demircioğlu,et al.  Theoretical analysis (NBO, NPA, Mulliken Population Method) and molecular orbital studies (hardness, chemical potential, electrophilicity and Fukui function analysis) of (E)-2-((4-hydroxy-2-methylphenylimino)methyl)-3-methoxyphenol , 2015 .

[55]  W. Liu,et al.  Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019‐nCoV , 2020, Chembiochem : a European journal of chemical biology.

[56]  M. Pal,et al.  Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2): An Update , 2020, Cureus.

[57]  A. M. Leontovich,et al.  The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2 , 2020, Nature Microbiology.

[58]  Birgit Strodel,et al.  High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2 , 2020, Molecules.

[59]  Guangdi Li,et al.  Therapeutic options for the 2019 novel coronavirus (2019-nCoV) , 2020, Nature Reviews Drug Discovery.

[60]  N R Sheela,et al.  Molecular orbital studies (hardness, chemical potential and electrophilicity), vibrational investigation and theoretical NBO analysis of 4-4'-(1H-1,2,4-triazol-1-yl methylene) dibenzonitrile based on abinitio and DFT methods. , 2014, Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy.

[61]  B. Banaigs,et al.  Trichormamide C Structural Confirmation through Total Synthesis and Extension to Analogs. , 2019, Organic letters.

[62]  D. Cucinotta,et al.  WHO Declares COVID-19 a Pandemic , 2020, Acta bio-medica : Atenei Parmensis.

[63]  Olivier Michielin,et al.  SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules , 2017, Scientific Reports.

[64]  K. Park,et al.  Biflavonoids from Torreya nucifera displaying SARS-CoV 3CLpro inhibition , 2010, Bioorganic & Medicinal Chemistry.

[65]  G. Cordell,et al.  Cytotoxic biflavonoids from Selaginella willdenowii. , 1995, Phytochemistry.

[66]  S. H. Lee,et al.  Antiviral amentoflavone from Selaginella sinensis. , 2001, Biological & pharmaceutical bulletin.

[67]  Sang Gu Kang,et al.  Anti-dengue infectivity evaluation of bioflavonoid from Azadirachta indica by dengue virus serine protease inhibition , 2020, Journal of biomolecular structure & dynamics.