Identification of potential SARS-CoV-2 M^pro inhibitors integrating molecular docking and water thermodynamics

Abstract

The COVID-19 pandemic is an ongoing global health emergency caused by a newly discovered coronavirus SARS-CoV-2. The entire scientific community across the globe is working diligently to tackle this unprecedented challenge. In silico studies have played a crucial role in the current situation by expediting the process of identification of novel potential chemotypes targeting the viral receptors. In this study, we have made efforts to identify molecules that can potentially inhibit the SARS-CoV-2 main protease (M pro) using the high-resolution crystal structure of SARS-CoV-2 M pro. The SARS-CoV-2 M pro has a large flexible binding pocket that can accommodate various chemically diverse ligands but a complete occupation of the binding cavity is necessary for efficient inhibition and stability. We augmented glide three-tier molecular docking protocol with water thermodynamics to screen molecules obtained from three different compound libraries. The diverse hits obtained through docking studies were scored against generated WaterMap to enrich the quality of results. Five molecules were selected from each compound library on the basis of scores and protein-ligand complementarity. Further MD simulations on the proposed molecules affirm the stability of these molecules in the complex. MM-GBSA results and intermolecular hydrogen bond analysis also confirm the thermodynamic stability of proposed molecules. This study also presumably steers the structure determination of many ligandmain protease complexes using x-ray diffraction methods.

Antcin-B, a phytosterol-like compound from Taiwanofungus camphoratus inhibits SARS-CoV-2 3-chymotrypsin-like protease (3CLPro) activity in silico and in vitro

“…3 a–c 35 , 36 . These residues might explain the inhibitory activity of these compounds, as residues like Thr24 form a part of the catalytic site for the inhibition of 3CL pro 37 . However, antcin-B exhibits the best binding affinity energy, contacting 19 amino acids within the subsite binding cleft, including S1′-(Thr25 and Thr24), S1-(Glu166, Leu141, Phe140, Asn142, and His163), S2-(Met165, Met49, His41, S4-Gln189), which are mainly responsible for substrate binding 38 , whereas Cys44, Thr45, Ser46, Ser144, Cys145, and Arg188 are responsible for the enzyme dimeric structure of the 3CL pro and not conventional catalytic residues for the ligands, which might be the reason for better affinity binding than other compounds as shown in Table 1 .…”

Synthesis and Biological Evaluation of Benzothiazolyl-pyridine Hybrids as New Antiviral Agents against H5N1 Bird Flu and SARS-COV-2 Viruses

“…SARS-CoV-2 is composed of two overlapping polyproteins (pp1a and pp1ab) encoded in the RNA genome, whose cleavage is essential for replication and transcription processes . These cleavage processes are mediated by the major protease M pro (3-chymotrypsin-like protease 3CLpro) and nonstructural viral proteins such as the papain-like protease PLpro. − In this regard, inhibition of viral RNA synthesis is considered as one way to combat coronaviruses …”

Cryo-Ground Mango Kernel Powder: Characterization, LC-MS/MS Profiling, Purification of Antioxidant-Rich Gallic Acid, and Molecular Docking Study of Its Major Polyphenols as Potential Inhibitors against SARS-CoV-2 Mpro

“… 25 Thus, this calls for the need for predicting plausible drug candidates from natural sources to inhibit COVID-19 virus, and this could be explored using molecular docking. 26 Molecular docking is a technique for computer-aided drug design by docking a ligand with the receptor’s active site. It describes the actual site of compound interaction and also reveals the names of amino acids involved in the interaction.…”

“…Bioactive components from natural sources might enhance immunity and reduce the chance of the occurrence of this disease . Thus, this calls for the need for predicting plausible drug candidates from natural sources to inhibit COVID-19 virus, and this could be explored using molecular docking . Molecular docking is a technique for computer-aided drug design by docking a ligand with the receptor’s active site.…”