Synthesis, crystal structure, and a molecular modeling approach to identify effective antiviral hydrazide derivative against the main protease of SARS-CoV-2

Shaaban K Mohamed; Youness El Bakri; Dalia A Abdul; Sajjad Ahmad; Mustafa R Albayati; Chin-Hung Lai; Joel T Mague; Mahmoud S Tolba

doi:10.1016/j.molstruc.2022.133391

Synthesis, crystal structure, and a molecular modeling approach to identify effective antiviral hydrazide derivative against the main protease of SARS-CoV-2

J Mol Struct. 2022 Oct 5:1265:133391. doi: 10.1016/j.molstruc.2022.133391. Epub 2022 May 28.

Authors

Shaaban K Mohamed^{1

2}, Youness El Bakri³, Dalia A Abdul⁴, Sajjad Ahmad⁵, Mustafa R Albayati⁶, Chin-Hung Lai^{7

8}, Joel T Mague⁹, Mahmoud S Tolba¹⁰

Affiliations

¹ Chemistry and Environmental Division, Manchester Metropolitan University, Manchester M1 5GD, United Kingdom.
² Chemistry Department, Faculty of Science, Minia University, 61519 El-Minia, Egypt.
³ Department of Theoretical and Applied Chemistry, South Ural State University, Lenin prospect 76, Chelyabinsk 454080, Russia.
⁴ Department of Chemistry, College of Science, university of Sulaimani, Sulaimania, Iraq.
⁵ Department of Health and Biological Sciences, Abasyn University, Peshawar 25000, Pakistan.
⁶ Kirkuk University, College of Science, Department of Chemistry, Kirkuk, Iraq.
⁷ Department of Medical Applied Chemistry, Chung Shan Medical University, Taichung 40241, Taiwan.
⁸ Department of Medical Education, Chung Shan Medical University Hospital, 402 Taichung, Taiwan.
⁹ Department of Chemistry, Tulane University, New Orleans, LA 70118, United States.
¹⁰ Chemistry Department, Faculty of Science, New Valley University, El-Kharja 72511, Egypt.

Abstract

In the fall of 2019, a new type of coronavirus took place in Wuhan city, China, and rapidly spread across the world and urges the scientific community to develop antiviral therapeutic agents. In our effort we have synthesized a new hydrazide derivative, (E)-N'-(1-(4-bromophenyl)ethylidene)-2-(6-methoxynaphthalen-2-yl)propanehydrazide for this purpose because of its potential inhibitory proprieties. The asymmetric unit of the title molecule consists of two independent molecules differing noticeably in conformation. In the crystal, the independent molecules are linked by N-H···O and C-H···O hydrogen bonds and C-H···π(ring) interactions into helical chains extending along the b-axis direction. The chains are further joined by additional C-H···π(ring) interactions into the full 3-D structure. To obtain a structure-activity relationship, the DFT-NBO analysis is performed to study the intrinsic electronic properties of the title compound. Molecular modeling studies were also conducted to examine the binding affinity of the compound for the SARS-CoV-2 main protease enzyme and to determine intermolecular binding interactions. The compound revealed a stable binding mode at the enzyme active pocket with a binding energy value of -8.1 kcal/mol. Further, stable dynamics were revealed for the enzyme-compound complex and reported highly favorable binding energies. The net MMGBSA binding energy of the complex is -37.41 kcal/mol while the net MMPBSA binding energy is -40.5 kcal/mol. Overall, the compound disclosed the strongest bond of ing the main protease enzyme and might be a good lead for further structural optimization.

Keywords: Crystal structurey; DFT calculations; Hydrazide; Molecular docking; Molecular dynamics simulations; SARS-CoV-2.