The human Mpox virus (hMPXV), an orthopoxvirus in the Poxviridae family, has emerged as a global health threat. Although smallpox therapeutics have been repurposed in the absence of hMPXV-specific drugs or vaccines, they suffer from efficacy limitations and lengthy development timelines. Modern computational approaches have streamlined lead identification and accelerated therapeutic development. This study targets thymidylate kinase (TMPK), which is an essential viral enzyme involved in DNA synthesis and genome replication. A hierarchical virtual screening of marine natural products (MNPs) from comprehensive marine natural products database (CMNPD) identified three hits (CMNPD10460, CMNPD28843, and CMNPD15724) with docking scores between -7.72 and -8.02 kcal/mol and molecular mechanics generalized born surface area binding energies in the range of -40 to -59.07 kcal/mol, indicating strong TMPK affinity. Their complexes are stabilized by hydrogen bonds as well as by hydrophobic and stacking interactions. All hits obeyed Lipinski's Rule of Five and exhibited favorable pharmacokinetic properties, including appropriate hydrogen bond donors and acceptors, human oral absorption, cardiotoxicity risk, blood-brain barrier penetration, and permeability across Madin-Darby canine kidney (MDCK) cells. Density functional theory analyses of the highest occupied molecular orbitals and lowest unoccupied molecular orbital energy gaps confirmed their chemical reactivity. Long-range 300 ns molecular dynamics simulations, principal component-based free energy landscape analysis, and define secondary structure of proteins based secondary-structure monitoring demonstrated the structural stability and conformational flexibility of TMPK-MNP complexes. These computational insights are expected to provide a solid foundation for experimental validation and the development of effective hMPXV therapeutics.
Jayaraman et al. (Tue,) studied this question.