Unveiling the molecular mechanism of SARS-CoV-2 main protease inhibition from 137 crystal structures using algebraic topology and deep learning

Nguyen, Duc Duy; Gao, Kaifu; Chen, Jiahui; Wang, Rui; Wei, Guowei

doi:10.1039/d0sc04641h

Cited by 68 publications

(67 citation statements)

References 39 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The other favorable amino acid interactions are HIS163, and PRO168 seems to play a vital role in most of the ligands within the M pro active pocket. Recently in 2020, Nguyen et al [50] also unveiled the fact that Gly143, Cys145, Glu166, and His163 of M pro are the region to form a hydrogen bond and highly favorable molecular fragments for the development of novel SARS-CoV-2 main protease inhibitors, which resembles the finding in the current study. An in silico study performed by Srivastava et al demonstrates the binding stability of Glycyrrhiza glabra derivatives, i.e., GA as bioactive inhibitor inside the SARS-CoV-2 M pro and proposed HIS41, GLY143, GLN189, GLU166, CYS145, THR25, ASN142, MET49, and PRO168 present in the active site of M pro were shown to make non-covalent interaction with the target compound, which was found consistent with our observation [51].…”

Section: Binding Interactions Of Potential Antiviral Agents At the Acsupporting

confidence: 83%

Molecular docking, binding mode analysis, molecular dynamics, and prediction of ADMET/toxicity properties of selective potential antiviral agents against SARS-CoV-2 main protease: an effort toward drug repurposing to combat COVID-19

et al. 2021

View full text Add to dashboard Cite

The importance of the main protease (M pro) enzyme of SARS-CoV-2 in the digestion of viral polyproteins introduces M pro as an attractive drug target for antiviral drug design. This study aims to carry out the molecular docking, molecular dynamics studies, and prediction of ADMET properties of selected potential antiviral molecules. The study provides an insight into biomolecular interactions to understand the inhibitory mechanism and the spatial orientation of the tested ligands and further, identification of key amino acid residues within the substrate-binding pocket that can be applied for structure-based drug design. In this regard, we carried out molecular docking studies of chloroquine (CQ), hydroxychloroquine (HCQ), remdesivir (RDV), GS441524, arbidol (ARB), and natural product glycyrrhizin (GA) using AutoDock 4.2 tool. To study the drug-receptor complex's stability, selected docking possesses were further subjected to molecular dynamics studies with Schrodinger software. The prediction of ADMET/toxicity properties was carried out on ADMET Prediction™. The docking studies suggested a potential role played by CYS145, HIS163, and GLU166 in the interaction of molecules within the active site of COVID-19 M pro. In the docking studies, RDV and GA exhibited superiority in binding with the crystal structure of M pro over the other selected molecules in this study. Spatial orientations of the molecules at the active site of M pro exposed the significance of S1-S4 subsites and surrounding amino acid residues. Among GA and RDV, RDV showed better and stable interactions with the protein, which is the reason for the lesser RMSD values for RDV. Overall, the present in silico study indicated the direction to combat COVID-19 using FDA-approved drugs as promising agents, which do not need much toxicity studies and could also serve as starting points for lead optimization in drug discovery.

show abstract

Section: Binding Interactions Of Potential Antiviral Agents At the Acsupporting

confidence: 83%

Molecular docking, binding mode analysis, molecular dynamics, and prediction of ADMET/toxicity properties of selective potential antiviral agents against SARS-CoV-2 main protease: an effort toward drug repurposing to combat COVID-19

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The Glu166 anchor hooks the ligand tightly to the central region of the binding site, which facilitate the formation of further interactions with other residues. Gly143 of SARS-CoV-2 3CL pro was reported to be the most favorable residue to form hydrogen bonds with ligands, followed by Glu166, Cys145, and His163 [37]. The amides of Gly143, Cys145, and Ser144 form the cysteine protease's canonical "oxyanion hole".…”

Section: Discussionmentioning

confidence: 99%

Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations

Ahmad

Batool

Ain

et al. 2021

IJMS

View full text Add to dashboard Cite

The novel coronavirus disease, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), rapidly spreading around the world, poses a major threat to the global public health. Herein, we demonstrated the binding mechanism of PF-07321332, α-ketoamide, lopinavir, and ritonavir to the coronavirus 3-chymotrypsin-like-protease (3CLpro) by means of docking and molecular dynamic (MD) simulations. The analysis of MD trajectories of 3CLpro with PF-07321332, α-ketoamide, lopinavir, and ritonavir revealed that 3CLpro–PF-07321332 and 3CLpro–α-ketoamide complexes remained stable compared with 3CLpro–ritonavir and 3CLpro–lopinavir. Investigating the dynamic behavior of ligand–protein interaction, ligands PF-07321332 and α-ketoamide showed stronger bonding via making interactions with catalytic dyad residues His41–Cys145 of 3CLpro. Lopinavir and ritonavir were unable to disrupt the catalytic dyad, as illustrated by increased bond length during the MD simulation. To decipher the ligand binding mode and affinity, ligand interactions with SARS-CoV-2 proteases and binding energy were calculated. The binding energy of the bespoke antiviral PF-07321332 clinical candidate was two times higher than that of α-ketoamide and three times than that of lopinavir and ritonavir. Our study elucidated in detail the binding mechanism of the potent PF-07321332 to 3CLpro along with the low potency of lopinavir and ritonavir due to weak binding affinity demonstrated by the binding energy data. This study will be helpful for the development and optimization of more specific compounds to combat coronavirus disease.

show abstract

“…Drugs that specifically bind to and inhibit SARS-CoV-2 M pro could be promising alternatives to fight the pandemic. Gly 143 of SARS-CoV-2 M pro is reported to be the most attractive residue to form hydrogen bonds with ligands followed by Glu 166 , Cys 145 , and His 163 ( Nguyen et al, 2020 ). Therefore, determining the crystal structure of viral proteases in a complex with potential inhibitors is vital as it provides a glimpse into designing improved drugs through the modification of the inhibitors according to the structural dynamics (monomer or dimer, narrow or wide, deep or shallow) of the active site in the target enzymes.…”

Section: Structure-based Design Of Drugs That Target Sars-cov-2 M Promentioning

confidence: 99%

Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

2021

View full text Add to dashboard Cite

The Coronavirus disease-19 (COVID-19) pandemic is still devastating the world causing significant social, economic, and political chaos. Corresponding to the absence of globally approved antiviral drugs for treatment and vaccines for controlling the pandemic, the number of cases and/or mortalities are still rising. Current patient management relies on supportive treatment and the use of repurposed drugs as an indispensable option. Of a crucial role in the viral life cycle, ongoing studies are looking for potential inhibitors to the main protease (Mpro) of severe acute respiratory syndrome Coronavirus -2 (SARS-CoV-2) to tackle the pandemic. Although promising results have been achieved in searching for drugs inhibiting the Mpro, work remains to be done on designing structure-based improved drugs. This review discusses the structural basis of potential inhibitors targeting SARS-CoV-2 Mpro, identifies gaps, and provides future directions. Further, compounds with potential Mpro based antiviral activity are highlighted.

show abstract

Unveiling the molecular mechanism of SARS-CoV-2 main protease inhibition from 137 crystal structures using algebraic topology and deep learning

Abstract: Currently, there is no effective antiviral drugs nor vaccine for coronavirus disease 2019 (COVID-19)caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to its high conservativeness andlow similarity with human...

Cited by 68 publications

References 39 publications

Molecular docking, binding mode analysis, molecular dynamics, and prediction of ADMET/toxicity properties of selective potential antiviral agents against SARS-CoV-2 main protease: an effort toward drug repurposing to combat COVID-19

Molecular docking, binding mode analysis, molecular dynamics, and prediction of ADMET/toxicity properties of selective potential antiviral agents against SARS-CoV-2 main protease: an effort toward drug repurposing to combat COVID-19

Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations

Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

Contact Info

Product

Resources

About