Novel phytochemical inhibitors targeting monkeypox virus thymidine and serine/threonine kinase: integrating computational modeling and molecular dynamics simulation

Abstract

Due to the rapid spread of the monkeypox virus and rise in the number of cases, there is an urgent need for the development of effective drugs against the infection. Serine/threonine protein kinase (Ser/Thr kinase) and Thymidine Kinase (TK) plays an imperative role in the replication and virulence of monkeypox virus and thus is deliberated as an attractive target in anti-viral drug development. In the present study, the 3D structure of monkeypox virus Ser/Thr kinase and TK was generated via molecular modeling techniques and performed their thorough structural analysis. We have screened potent anti-viral phytochemicals from the literature to inhibit Ser/Thr kinase and TK. As part of the initial screening, the physicochemical properties of the compounds were examined. Following this, a structure-based molecular docking technique was used to select compounds based on their binding affinity towards Ser/Thr kinase and TK. In order to find more potent hits against Ser/Thr kinase and TK, further examinations of ADMET properties, PAINS patterns and blood–brain barrier permeability were conducted. As a result, thalimonine and galanthamine were identified from the screening process bearing appreciable binding affinity towards Ser/Thr kinase and TK respectively, which showed a worthy set of drug-like properties. In the end, molecular dynamics simulations were performed for 100 ns, which showed decent stability of both protein–ligand complex throughout the trajectory. Due to the possibility that both monkeypox virus target proteins may be inhibited by thalimonine and galanthamine, our study highlights the need to investigate in vivo effects of thalimonine and galanthamine.Communicated by Ramaswamy H. Sarma