Author:
Sun Chuancai,Zhang Jian,Wei Jiao,Zheng Xiaoli,Zhao Xianyang,Fang Zengjun,Xu Dongmei,Yuan Huiqing,Liu Yipeng
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak is a public health emergency of international concern. The spike glycoprotein (S protein) of SARS-CoV-2 is a key target of antiviral drugs. Focusing on the existing S protein structure, molecular docking was used in this study to calculate the binding energy and interaction sites between 14 antiviral molecules with different structures and the SARS-CoV-2 S protein, and the potential drug candidates targeting the SARS-CoV-2 S protein were analyzed. Tizoxanide, dolutegravir, bictegravir, and arbidol were found to have high binding energies, and they effectively bind key sites of the S1 and S2 subunits, inhibiting the virus by causing conformational changes in S1 and S2 during the fusion of the S protein with host cells. Based on the interactions among the drug molecules, the S protein and the amino acid environment around the binding sites, rational structure-based optimization was performed using the molecular connection method and bioisosterism strategy to obtain Ti-2, BD-2, and Ar-3, which have much stronger binding ability to the S protein than the original molecules. This study provides valuable clues for identifying S protein inhibitor binding sites and the mechanism of the anti-SARS-CoV-2 effect as well as useful inspiration and help for the discovery and optimization of small molecule S protein inhibitors.
Funder
National Natural Science Foundation of China
Third Project of Jinan City Science and Technology Development Plan
Young Taishan Scholars Program
Academic Promotion Programme of Shandong First Medical University
Natural Science Foundation of Shandong Province
Publisher
Public Library of Science (PLoS)
Reference33 articles.
1. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China;D Wang;JAMA,2020
2. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia;Q Li;The New England journal of medicine,2020
3. Return of the Coronavirus: 2019-nCoV;L Gralinski;Viruses,2020
4. Coronavirus disease (COVID-19) Weekly Epidemiological Update and Weekly Operational Update; World Health Organization: Geneva, 2020; https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports (accessed 20 December 2020).
5. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro;M Wang;Cell research,2020
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