The need for more advanced and effective
monkeypox (
Mpox) treatments has become evident with numerous Mpox virus (MPXV) outbreaks. Over the years, interest has increased in developing targeted medicines that are efficient, safe, and precise while avoiding adverse effects. Here, we screened 32409 compounds against
thymidylate kinase (TMPK), an emerging target for
Mpox treatment. We studied their pharmacological characteristics and analyzed those through all-atom molecular dynamics simulations followed by molecular mechanics Poisson Boltzmann surface area (MM-
PBSA) based free energy calculations. According to our findings, the leads CID40777874 and CID28960001 had the highest binding affinities towards TMPK with ΔGbind of -8.04 and -5.58 kcal/mol, respectively, which outperformed our control drug
cidofovir (ΔGbind = -2.92 kcal/mol) in terms of binding favourability. Additionally, we observed crucial TMPK dynamics brought on by
ligand-binding and identified key residues such as Phe68 and Tyr101 as the critical points of the
protein-
ligand interaction. The DCCM analysis revealed the role of
ligand binding in stabilizing TMPK's binding region, as indicated by residual correlation motions. Moreover, the PSN analysis revealed that the interaction with
ligand induces changes in residual network properties, enhancing the stability of complexes. We successfully identified novel compounds that may serve as potential building blocks for constructing contemporary
antivirals against MPXV and highlighted the molecular mechanisms underlying their binding with TMPK. Overall, our findings will play a significant role in advancing the development of new
therapies against
Mpox and facilitating a comprehensive understanding of their interaction patterns.Communicated by Ramaswamy H. Sarma.