The angiotensin-converting enzyme 2 (ACE2) and main protease (MPro), are the putative drug candidates for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, we performed 3D-QSAR pharmacophore modeling and screened 1,264,479 ligands gathered from Pubchem and Zinc databases. Following the calculation of the ADMET properties, molecular docking was carried out. Moreover, the ligand design was performed. MD simulation was then applied to survey the behavior of the ligand-protein complexes. Furthermore, MMPBSA has utilized to re-estimate the binding affinities. Then, a free energy landscape was used to find the most stable conformation of the complexes. Finally, the hybrid QM-MM method was carried out for the precise calculation of the energies. The Hypo1 pharmacophore model was selected as the best model. Our docking results indicate that the compounds ZINC12562757 and 112,260,215 were the best potential inhibitors of the ACE2 and MPro, respectively. Furthermore, the Evo_1 compound enjoys the highest docking energy among the designed ligands. Results of RMSD, RMSF, H-bond, and DSSP analyses have demonstrated that the lead compounds preserve the stability of the complexes' conformation during the MD simulation. MMPBSA data confirmed the molecular docking results. The results of QM-MM showed that Evo_1 has a stronger potential for specific inhibition of MPro, as compared to the 112,260,215 compound.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023563PMC
http://dx.doi.org/10.1016/j.molstruc.2021.130409DOI Listing

Publication Analysis

Top Keywords

angiotensin-converting enzyme
8
main protease
8
molecular docking
8
identification novel
4
novel inhibitors
4
inhibitors human
4
human angiotensin-converting
4
enzyme main
4
protease sars-cov-2
4
sars-cov-2 combination
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!