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.
Highlights
The ongoing novel coronavirus 2019 outbreak has been recently taken place and hit almost all over the world
To identify new inhibitor compounds, crystal x-ray structure of Angiotensin-converting enzyme 2 (ACE2) protein (PDB ID: 1R4L) in complex with ligand XX5 was retrieved from the Protein Data Bank (PDB), and a 3DSBPM to the enzymatic cavity was generated
The automatic key chemical features option of the advance tool determines and displayed a total 16, including 12 main and four dedicated pharmacophore features (Fig. 2), where two hydrogen bond donor (HBD), five hydrogen bond acceptor (HBA), two negative ionizable (NI), one positive ionizable (PI) area, two hydrophobic (H) interactions features have defined as main, and two aromatic rings (AR), one zinc-binding location (ZNB), and one halogen bond donor (XBD) features have defined as dedicated pharmacophore features of the protein-ligand complex interaction
Summary
The ongoing novel coronavirus 2019 (nCoV-2019) outbreak has been recently taken place and hit almost all over the world. The disease has been named COVID-19 (Coronavirus disease 2019) by the World Health Organization (WHO) recently after the outbreak started in Wuhan, Hubei province of China on 31 December 2019 [1]. The International Committee on Taxonomy of Viruses (ICTV) renamed the outbreak causing virus as to sever acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [2], responsible for lower respiratory tract disease of human [3]. COVID-19 pandemic is a great threat to both tropical and polar regions of the world [4], and WHO decreed the disease as a sixth public health emergency. The transmissible and pathogenic virus infects an estimated > 7,436,895 people and caused 417,861 confirmed deaths (June 10, 2020, 21:38 GMT) across 213 countries and territories around the world and 2 international conveyances [6]. To date, no specific proven drugs, vaccines, and therapeutics have been developed that, can prevent or treat infections resulting from these pathogens [8], [9]
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