Chloroquine and hydroxychloroquine inhibitors for COVID-19 sialic acid cellular receptor: Structure, hirshfeld atomic charge analysis and solvent effect

Tariq A Altalhi; Khaled Alswat; Walaa F Alsanie; Mohamed M Ibrahim; Ali Aldalbahi; Hamdy S El-Sheshtawy

doi:10.1016/j.molstruc.2020.129459

Chloroquine and hydroxychloroquine inhibitors for COVID-19 sialic acid cellular receptor: Structure, hirshfeld atomic charge analysis and solvent effect

J Mol Struct. 2021 Mar 15:1228:129459. doi: 10.1016/j.molstruc.2020.129459. Epub 2020 Oct 15.

Authors

Tariq A Altalhi¹, Khaled Alswat², Walaa F Alsanie³, Mohamed M Ibrahim^{1

4}, Ali Aldalbahi⁵, Hamdy S El-Sheshtawy⁴

Affiliations

¹ Department of Chemistry, Collage of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
² Department of internal medicine, Collage of medicine, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
³ Department of Clinical Laboratories Science, Collage of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
⁴ Chemistry Department, Faculty of Science, Kafrelsheikh University, 33516 Kafr ElSheikh, Egypt.
⁵ Department of Chemistry, College of Sciences, King Saud University, Riyadh 11451, Saudi Arabia.

Abstract

COVID-19, the pandemic disease recently discovered in Wuhan (China), severely spread and affected both social and economic activity all over the world. Attempts to find an effective vaccine are challenging, time-consuming though interminable. Hence, re-proposing effective drugs is reliable and effective alternative. Taking into account the genome similarity of COVID-19 with SARS-CoV, drugs with safety profiles could be fast solution. Clinical trials encouraged the use of Chloroquine and Hydroxychloroquine for COVID-19 inhibition. One of the possible inhibition pathways is the competitive binding with the angiotension-converting enzyme-2 (ACE-2), in particular with the cellular Sialic acid (Neu5Ac). Here, we investigate the possible binding mechanism of ClQ and ClQOH with sialic acid both in the gas phase and in water using density functional theory (DFT). We investigated the binding of the neutral, monoprotonated and diprotonated ClQs and ClQOHs to sialic acid to simulate the pH effect on the cellular receptor binding. DFT results reveals that monoprotonated ClQ⁺ and ClQOH⁺, which account for more than 66% in the solution, possess high reactivity and binding towards sialic acid. The Neu5Ac-ClQ and the analogues Neu5Ac-ClQOH adducts were stabilized in water than in the gas phase. The molecular complexes stabilize by strong hydrogen bonding and π - π stacking forces. In addition, proton-transfer in Neu5Ac-ClQOH⁺ provides more stabilizing power and cellular recognition binding forces. These results shed light on possible recognition mechanism and help future breakthroughs for COVID-19 inhibitors.

Keywords: COVID-19; Chloroquine; DFT calculations; Hydroxychloroquine; Sialic acid.