The study of antiviral drugs targeting SARS-CoV-2 nucleocapsid and spike proteins through large-scale compound repurposing

Hu, Xuqiao; Zhou, Zhenru; Li, Fei; Xiao, Yang; Wang, Zhaoyang; Xu, Jinfeng; Dong, Fajin; Zheng, Hairong; Yu, Rongmin

Contributing to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clinical treatment, a drug library encompassing approximately 3,142 clinical-stage or FDA-approved small molecules is profiled to identify the candidate therapeutic inhibitors targeting nucleocapsid protein (N) and spike protein (S) of SARS-CoV-2. 16 screened candidates with higher binding affinity are evaluated via virtual screening. Comparing to those under trial/temporarily used antivirus drugs (i.e., umifenovir, lopinavir), ceftriaxone, cefotaxime, and cefuroxime show higher binding affinities to the N-terminal domain of N protein (N-NTD), C-terminal domain of N protein (N-CTD), and receptor-binding domain of S protein (S-RBD). Cefotaxime and cefuroxime have high binding affinities towards S-RBD with angiotensin-converting enzyme 2 (ACE2) complex via influence the critical interface sites at the interface of S-RBD (Arg(403), Tyr(453), Trp(495), Gly(496), Phe(497), Asn(501)and Tyr(505)) and ACE2 (Asn(33), His(34), Glu(37), Asp(38), Lys(353), Ala(386), Ala(387), Gln(388), Pro(389), Phe(390) and Arg(393)) complex.