Identification of compelling inhibitors of human norovirus 3CL protease to combat gastroenteritis: A structure-based virtual screening and molecular dynamics study

Shan He; Alaa F Nahhas; Alaa Hamed Habib; Mohammed Ali Alshehri; Saleh Alshamrani; Saeed A Asiri; Mashael M Alnamshan; Nawal Helmi; Ibtesam Al-Dhuayan; Jawaher Almulhim; Ahmed M Alharbi; Dongxiao Su; Ankita Kumari; Abdul Rahaman

doi:10.3389/fchem.2022.1034911

Identification of compelling inhibitors of human norovirus 3CL protease to combat gastroenteritis: A structure-based virtual screening and molecular dynamics study

Front Chem. 2022 Sep 30:10:1034911. doi: 10.3389/fchem.2022.1034911. eCollection 2022.

Authors

Shan He^{1

2

3}, Alaa F Nahhas⁴, Alaa Hamed Habib⁵, Mohammed Ali Alshehri⁶, Saleh Alshamrani⁶, Saeed A Asiri⁶, Mashael M Alnamshan⁷, Nawal Helmi^{8

9}, Ibtesam Al-Dhuayan⁷, Jawaher Almulhim¹⁰, Ahmed M Alharbi¹¹, Dongxiao Su¹, Ankita Kumari¹², Abdul Rahaman¹²

Affiliations

¹ School of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou, China.
² Institute for Nano Scale and Technology, College of Science and Engineering, Flinders University, Adelaide, SA, Australia.
³ Suzhou Ultra-Water-Cleaning Tech, Pty, Ltd., Suzhou, Jiangsu, China.
⁴ Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
⁵ Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
⁶ Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Najran University, Najran, Saudi Arabia.
⁷ Department of Biology, College of Science, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.
⁸ Department of Biochemistry, College of Science, University of Jeddah, Jeddah, Saudi Arabia.
⁹ Department of Medical Laboratory Technology, College of Applied Medical Sciences, University of Jeddah, Jeddah, Saudi Arabia.
¹⁰ Department of Biological Sciences, King Faisal University, Alahsa, Saudi Arabia.
¹¹ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail, Saudi Arabia.
¹² School of Food Science and Engineering, South china University of Technology, Guangzhou, China.

Abstract

Human noroviruses (NV) are the most prevalent cause of sporadic and pandemic acute gastroenteritis. NV infections cause substantial morbidity and death globally, especially amongst the aged, immunocompromised individuals, and children. There are presently no authorized NV vaccines, small-molecule therapies, or prophylactics for humans. NV 3 C L protease (3CLP) has been identified as a promising therapeutic target for anti-NV drug development. Herein, we employed a structure-based virtual screening method to screen a library of 700 antiviral compounds against the active site residues of 3CLP. We report three compounds, Sorafenib, YM201636, and LDC4297, that were revealed to have a higher binding energy (BE) value with 3CLP than the control (Dipeptidyl inhibitor 7) following a sequential screening, in-depth molecular docking and visualization, physicochemical and pharmacological property analysis, and molecular dynamics (MD) study. Sorafenib, YM201636, and LDC4297 had BEs of -11.67, -10.34, and -9.78 kcal/mol with 3CLP, respectively, while control had a BE of -6.38 kcal/mol. Furthermore, MD simulations of the two best compounds and control were used to further optimize the interactions, and a 100 ns MD simulation revealed that they form stable complexes with 3CLP. The estimated physicochemical, drug-like, and ADMET properties of these hits suggest that they might be employed as 3CLP inhibitors in the management of gastroenteritis. However, wet lab tests are a prerequisite to optimize them as NV 3CLP inhibitors.

Keywords: gastroenteritis; molecular dynamics; natural compounds; noroviruses; protease.