Importance of glutamine 189 flexibility in SARS-CoV-2 main protease: Lesson learned from in silico virtual screening of ChEMBL database and molecular dynamics

Abstract

The current global pandemic outbreak of COVID-19 caused by the SARS-CoV-2 strike an invincible damage to both daily life and the global economy. WHO guidelines for COVID-19 clinical management includes infection control and prevention, social distancing and supportive care using supplemental oxygen and mechanical ventilator support. Currently, evolving researches and clinical reports regarding infected patients with SARS-CoV-2 suggest a potential list of repurposed drugs that may produce appropriate pharmacological therapeutic efficacies in treating COVID-19 infected patients. In this study, we performed virtual screening and evaluated the obtained results of US-FDA approved small molecular database library (302 drug molecule) against two important different protein targets in COVID-19. Best compounds in molecular docking were used as a training set for generation of two different pharmacophores. The obtained pharmacophores were employed for virtual screening of ChEMBL database. The filtered compounds were clustered using Finger print model to obtain two compounds that will be subjected to molecular docking simulations against the two targets. Compounds complexes with SARS-CoV-2 main protease and S-protein were studied using molecular dynamics (MD) simulation. MD simulation studies suggest the potential inhibitory activity of ChEMBL398869 against SARS-CoV-2 main protease and restress the importance of Gln189 flexibility in inhibitors recognition through increasing S2 subsite plasticity.

In silico analysis and identification of antiviral coumarin derivatives against 3-chymotrypsin-like main protease of the novel coronavirus SARS-CoV-2

“…3 and Fig. S5) [1,18,32,43,51]. The selected compounds and Ritonavir and lopinavir exhibit similar binding modes due to the parallel orientations of the ligands and their same key residues (Fig.…”

“…Within MOE, the flexibility of ligands is considered while the proteins are considered as a rigid structure. Site finder [32][33][34] was used for the selection of the active site of the 3CLpro protein and the active site was defined with at least one atom within a distance cut off of 4.5 Å at ligand in the crystal structure of 3CLpro. The docking was done using the triangle matcher placement algorithm in combination with the London dG scoring function and force field as the refinement method.…”

“…The topology files of glycycoumarin, Inophyllum P, oxypeucedanin hydrate, N3, and lopinavir were obtained from the PRODRG server [45] while the topology file of 3CLpro protein was prepared by the GROMACS. The 3CLpro and 3CLpro-ligand systems were solvated and fully immersed in the dodecahedron box with simple point charge (SPC) waters and neutralized by adding four sodium ions and energy minimized using the steepest descent algorithm [1,15,18,32] for 50,000 steps and energy tolerance of 500 kJ/mol in a periodic boundary condition and equilibrated to achieve the appropriate volume under NVT ensemble [46]. The particle-Mesh Ewald (PME) method was used with a Fourier grid spacing of 1 Å to calculate the long-range electrostatic interactions.…”

Anti-Inflammatory, Antiallergic, and COVID-19 Main Protease (Mpro) Inhibitory Activities of Butenolides from a Marine-Derived Fungus Aspergillus terreus

“…It was found to interact with several amino acids in the active site, including Phe140, Gly143, His163, His164, Glu166, Gln189, and Thr190. Several research groups investigated synthetic and natural products for their inhibition of this target among other SARS-CoV-2 targets [36][37][38]. We have previously used the same target to investigate the potential inhibition of phytochemicals from In addition to the human NE, we were also interested in investigating the potential binding and inhibitory activities of isolated compounds against SARS-CoV-2 main protease (M pro ) owing to the current pandemic situation.…”

2-Arylquinolines as novel anticancer agents with dual EGFR/FAK kinase inhibitory activity: synthesis, biological evaluation, and molecular modelling insights

“…Missing loops in the 3D structures of the protein were constructed using Swiss-Model 43 before starting molecular dynamics steps. All atom molecular dynamics simulations were performed using GROMACS 2020.3 53 for the selected protein-ligand complexes as reported earlier 54 . In brief, SwissParam server 55 was used for ligands parameterisation while Charmm36 all-atom force field 56 was used to generate topology files for the protein.…”