Discovery of Novel Small-Molecule Inhibitors of SARS-CoV-2 Main Protease as Potential Leads for COVID-19 Treatment

被引：17

作者：

Manandhar, Anjela ^{[1
,2
]}

Srinivasulu, Vunnam ^{[3
]}

Hamad, Mohamad ^{[3
]}

Tarazi, Hamadeh ^{[4
]}

Omar, Hany ^{[3
,4
]}

Colussi, Dennis J. ^{[5
]}

Gordon, John ^{[5
]}

Childers, Wayne ^{[5
]}

Klein, Michael L. ^{[1
,2
]}

Al-Tel, Taleb H. ^{[3
,4
]}

Abou-Gharbia, Magid ^{[5
]}

Elokely, Khaled M. ^{[1
,2
,6
]}

机构：

[1] Temple Univ, Inst Computat Mol Sci, Philadelphia, PA 19122 USA

[2] Temple Univ, Dept Chem, Philadelphia, PA 19122 USA

[3] Univ Sharjah, Sharjah Inst Med Res, Sharjah 27272, U Arab Emirates

[4] Univ Sharjah, Coll Pharm, Sharjah 27272, U Arab Emirates

[5] Temple Univ, Moulder Ctr Drug Discovery Res, Sch Pharm, Dept Pharmaceut Sci, Philadelphia, PA 19122 USA

[6] Tanta Univ, Dept Pharmaceut Chem, Tanta 31527, Egypt

来源：

JOURNAL OF CHEMICAL INFORMATION AND MODELING | 2021年 / 61卷 / 09期

基金：

美国国家科学基金会;

关键词：

DYNAMICS; SARS; IDENTIFICATION; DESIGN; PREDICTION; DOCKING;

D O I：

10.1021/acs.jcim.1c00684

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The main protease of SARS-CoV-2 virus, M-pro is an essential element for viral replication, and inhibitors targeting M-pro are currently being investigated in many drug development programs as a possible treatment for COVID-19. An in vitro pilot screen of a highly focused collection of compounds was initiated to identify new lead scaffolds for M-pro. These efforts identified a number of hits. The most effective of these was compound SIMR-2418 having an inhibitory IC50 value of 20.7 mu M. Molecular modeling studies were performed to understand the binding characteristics of the identified compounds. The presence of a cyclohexenone warhead group facilitated covalent binding with the Cys(145) residue of M-pro. Our results highlight the challenges of targeting M-pro protease and pave the way toward the discovery of potent lead molecules.

引用

页码：4745 / 4757

页数：13

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