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

Shweta Choudhary, Yashpal S. Malik, Shailly Tomar

10.3389/fimmu.2020.01664

Research curated

Abstract

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 cellular angiotensin converting enzyme 2 (ACE2) receptor. 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 toward exponentially expanding COVID-19. Thereto, high throughput virtual screening approach was used to investigate FDA approved LOPAC library drugs against both the receptor binding domain of spike protein (S-RBD) and ACE2 host cell receptor. Primary screening identified a few promising molecules for both the targets, which were further analyzed in details by their binding energy, binding modes through molecular docking, dynamics and simulations. Evidently, GR 127935 hydrochloride hydrate, GNF-5, RS504393, TNP, and eptifibatide acetate were found binding to virus binding motifs of ACE2 receptor. Additionally, KT203, BMS195614, KT185, RS504393, and GSK1838705A were identified to bind at the receptor binding site on the viral S-protein. These identified molecules may effectively assist in controlling the rapid spread of SARS-CoV-2 by not only potentially inhibiting the virus at entry step but are also hypothesized to act as anti-inflammatory agents, which could impart relief in lung inflammation. 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 efficiency by these molecules could save lives is justified.

Source: PubMed

Related molecules

Name	Synonyms	Genes
RS504393	6-Methyl-1'-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)spiro[benzo[d][1,3]oxazine-4,4'-piperidin]-2(1H)-one, RS 504393, RS-504393
KT185	CHEMBL3263579, (2-Phenyl-1-piperidinyl)[4-[3'-(1-piperidinylcarbonyl)-4-biphenylyl]-1H-1,2,3-triazole-1-yl]methanone
GSK1838705A	2-((2-((1-(2-(Dimethylamino)acetyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide
BMS614	BMS 195614, BMS 614, 4-[(5,5-Dimethyl-8-quinolin-3-yl-6H-naphthalene-2-carbonyl)amino]benzoic acid
Eptifibatide acetate
Angiotensin-converting enzyme 2	ACE-related carboxypeptidase, ACE2	ACE2
Spike glycoprotein	Spike protein, S glycoprotein, S-Protein, S1, S2, S3, Peplomer protein, E2	S, ORF2

Related interactions

Target	Drug	Type	Result
Angiotensin-converting enzyme 2	RS504393	Computational	positive
Spike glycoprotein	RS504393	Computational	positive
Spike glycoprotein	KT185	Computational	positive
Spike glycoprotein	GSK1838705A	Computational	positive
Spike glycoprotein	BMS614	Computational	positive
Angiotensin-converting enzyme 2	Eptifibatide acetate	Computational	positive