ABSTRACT
Angiotensin-converting enzyme 2 (ACE2), also known as peptidyl-dipeptidase A, belongs to the dipeptidyl carboxydipeptidases family has emerged as a potential antiviral drug target against SARS-CoV-2. Most of the ACE2 inhibitors discovered till now are chemical synthesis; suffer from many limitations related to stability and adverse side effects. However, natural, and selective ACE2 inhibitors that possess strong stability and low side effects can be replaced instead of those chemicals' inhibitors. To envisage structurally diverse natural entities as an ACE2 inhibitor with better efficacy, a 3D structure-based-pharmacophore model (SBPM) has been developed and validated by 20 known selective inhibitors with their correspondence 1166 decoy compounds. The validated SBPM has excellent goodness of hit score and good predictive ability, which has been appointed as a query model for further screening of 11,295 natural compounds. The resultant 23 hits compounds with pharmacophore fit score 75.31 to 78.81 were optimized using in-silico ADMET and molecular docking analysis. Four potential natural inhibitory molecules namely D-DOPA (Amb17613565), L-Saccharopine (Amb6600091), D-Phenylalanine (Amb3940754), and L-Mimosine (Amb21855906) have been selected based on their binding affinity (-7.5, -7.1, -7.1, and -7.0 kcal/mol), respectively. Moreover, 250 ns molecular dynamics (MD) simulations confirmed the structural stability of the ligands within the protein. Additionally, MM/GBSA approach also used to support the stability of molecules to the binding site of the protein that also confirm the stability of the selected four natural compounds. The virtual screening strategy used in this study demonstrated four natural compounds that can be utilized for designing a future class of potential natural ACE2 inhibitor that will block the spike (S) protein dependent entry of SARS-CoV-2 into the host cell.