Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in Silico Structure-Based Virtual Screening Approach

Abstract

<jats:p>The rapidly spreading, highly contagious and pathogenic SARS-coronavirus 2 (SARS-CoV-2) associated Coronavirus Disease 2019 (COVID-19) has been declared as a pandemic by the World Health Organization (WHO). The novel 2019 SARS-CoV-2 enters the host cell by binding of the viral surface spike glycoprotein (S-protein) to angiotensin converting enzyme 2 (ACE2). The virus specific molecular interaction with the host cell represents a promising therapeutic target for identifying SARS-CoV-2 antiviral drugs. The repurposing of drugs can provide a rapid and potential cure towards exponentially expending COVID-19. Thereto, high-throughput virtual screening approach was used to investigate FDA approved LOPAC library drugs against both the S-protein and ACE2 host cell receptor. Primary screening identified a few promising drugs for both the targets, which were further analyzed in details by their binding energy, binding modes through molecular docking, dynamics and simulations. Evidently, Eptifibatide acetate, TNP, GNF5, GR 127935 hydrochloride hydrate and RS504393 were found binding to virus binding motifs of ACE2 receptor. Additionally, KT185, KT203 GSK1838705A, BMS195614, and RS504393 were identified to bind at the receptor binding site on the viral S-protein. These identified drug molecules may effectively assist in controlling the rapid spread of SARS-COV-2 by not only potentially inhibiting the virus at entry step but also as anti-inflammatory agents which could impart relief in lung injuries. Timely identification and determination of an effective drug to combat and tranquilize the COVID-19 global crisis is the utmost need of hour. Further, prompt in vivo testing to validate the anti-SARS-COV-2 inhibition by these drugs could save lives is justified.</jats:p>

Evaluation of Flavonoids as 2019-nCoV Cell Entry Inhibitor Through Molecular Docking and Pharmacological Analysis

“…whereas residues LEU 455, PHE 486 and SER 494 recognize hotspot LYS 353 [26,31]. It is also documented that SER494 of RBD of nCoV-SP strengthens the structural stability of hotspot LYS 353 of the human ACE-2 receptor [29].…”

“…Binding sites obtained from COACH-D was compared with identified binding sites of crystallized structure, PDB ID: 2GHV, which was already considered as a template for homology modeling for our query protein. Results generated from COACH server was further compared with previous studies on protein-protein docking, molecular dynamics and virtual screening studies on SARS-CoV-2 spike glycoprotein (nCoV-SP) as well human ACE-2 receptor [26][27][28][29][30][31][32]. The binding site residues, thus, selected from experimental studies as well as from bioinformatics tools thus provided a better platform for reliable docking studies.…”

“…Hence, predictive binding residues from COACH-D was compared with binding site residues from previous studies [26][27][28][29][30][31][32] and found that results from COACH-D were respectable for predicting important residues already documented and made our selection for the binding site more reliable and carry out our docking studies for interaction analysis.…”

“…Interaction studies revealed quercetin to interact with the residue ASP 38 of human ACE-2 receptor that formed the salt bridge with LYS 353 and forms the hotspot LYS353, which is utilized by the residues LEU 455, PHE 486 and SER494 of RBD of nCoV-SP with SER 494 additionally enhancing the stability of this hotspot (Fig. 3) [26,31]. In human ACE-2, without anyviral control or hold, LYS353 does not form any salt bridge with ASP 38, clearly indicating that the virus binding hotspot does not pre-exist on human ACE-2 and the salt bridge is only induced upon viral entry and load [26].…”

Origin, Potential Therapeutic Targets and Treatment for Coronavirus Disease (COVID-19)

“…ACE2 blockers can be another option to avoid the infection [106]. Similarly, there are some molecules including GSK1838705A, KT203, KT185, and BMS195614 that have strong binding affinities with RBD of the viral S-protein [107]. These molecules can help to control rapid infections by engaging the virus at entry points [107].…”