Abstract
This study aimed to identify potential inhibitors and investigate the mechanism of action on SARS-CoV-2 ACE2 receptors using a molecular modeling study and theoretical determination of biological activity. Hydroxychloroquine was used as a pivot structure and antimalarial analogues of 1,2,4,5 tetraoxanes were used for the construction and evaluation of pharmacophoric models. The pharmacophore-based virtual screening was performed on the Molport® database (~7.9 million compounds) and obtained 313 structures. Additionally, a pharmacokinetic study was developed, obtaining 174 structures with 99% confidence for human intestinal absorption and penetration into the blood–brain barrier (BBB); posteriorly, a study of toxicological properties was realized. Toxicological predictions showed that the selected molecules do not present a risk of hepatotoxicity, carcinogenicity, mutagenicity, and skin irritation. Only 54 structures were selected for molecular docking studies, and five structures showed binding affinity (ΔG) values satisfactory for ACE2 receptors (PDB 6M0J), in which the molecule MolPort-007-913-111 had the best ΔG value of −8.540 Kcal/mol, followed by MolPort-002-693-933 with ΔG = −8.440 Kcal/mol. Theoretical determination of biological activity was realized for 54 structures, and five molecules showed potential protease inhibitors. Additionally, we investigated the Mpro receptor (6M0K) for the five structures via molecular docking, and we confirmed the possible interaction with the target. In parallel, we selected the TopsHits 9 with antiviral potential that evaluated synthetic accessibility for future synthesis studies and in vivo and in vitro tests.
Highlights
The COVID-19 related pandemic is a fight that still needs to be fought by humanity, and beyond prevention by vaccination, the only way out is through the discovery of new drugs
Our study identified some potential candidates that can be used for the inhibition of
ADMET studies have revealed that most molecules have good absorption properties and low acute toxicity values
Summary
The main cause of the infection was found to be a new virus that has structural similarities with coronaviruses related to severe acute respiratory syndrome, called SARS-CoV-2 [1,2]. According to WHO data (https://www.who.int/emergencies/diseases/novel-coronavirus2019/situation-reports) (accessed on 28 January 2022) globally, the number of new COVID19 cases increased in the past week (17–23 January 2022) by 5%, while the number of new deaths remained similar to those reported during the previous week. As of 23 January 2022, over 346 million confirmed cases and over 5.5 million deaths were reported worldwide. The current global epidemiology of SARS-CoV-2 is characterized by the dominance of the Omicron variant on a global scale, continued decline in the prevalence of the Delta variant, and very low-level circulation of
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