The Hunt for antipox compounds against Monkeypox Virus Thymidylate Kinase and scaffolding protein leveraging Pharmacophore modeling, molecular docking, ADMET Studies, and molecular dynamics simulation studies

Abstract

Abstract Cases of the monkeypox virus have been recorded in non-endemic nations and have continued to be reported in several endemic nations since early May 2022 [1]. In this study, we modeled MPXV Thymidylate Kinase (TMPK) and scaffolding protein (D13), and these models and their templates were taken for small molecule screening against 602,413 small molecules using pharmacophore modeling and molecular docking methods. ADMET properties were also computed followed by Molecular simulation dynamics studies. All presented hits had superior molecular docking scores to used reference standards of Cidofovir and Rifampicin. TMPK compounds displayed better ADMET profiles than D13 compounds, hence the latter may necessitate optimization. Following molecular dynamics simulation, calculations of the RMSDs, RMSFs, Hydrogen Bonds, SASA, Radius of Gyration, MM-GBSA energy, PCA, and DCC revealed that all generated complexes were stable, with the ligands NPC275538, NPC244454, 135566871, and CHEBI compounds outperforming other Hits. These compounds still presented higher docking scores against cidofovir-resistant TMPK and Rifampicin-resistant D13 proteins. Compounds 447970, 446595, and 54723327 were most selective against human TMPK. The conserved interaction patterns of these compounds among Vaccinia and Monkeypox virus proteins with the fact that studied proteins are highly conserved across Orthopoxviruses (OPV) is appealing to the fact these hits should be studied across OPV. Therefore, these compounds should be subjected to laboratory testing to prove their antipox capability. Since there are currently no approved MPXV antivirals, this discovery significantly aids in developing new drugs for treating monkeypox.