Molecular modeling and simulation study of homoserine kinase as an effective leishmanial drug target.

Leishmaniasis is a tropical neglected disease that imposes major health concerns in many endemic countries worldwide and requires urgent attention to the identification of new drug targets as well as drug candidates. In the current study, we propose homoserine kinase (HSK) inhibition as a strategy to induce pathogen mortality via generating threonine deficiency. We introduce a homology-based molecular model of leishmanial HSK that appears to possess all conserved structural as well as functional features in the GHMP kinase family. Furthermore, 200 ns molecular dynamics data of the enzyme in open and closed state attempts to provide the mechanistic details involved in the substrate as well as phosphate binding to this enzyme. We discuss the structural and functional significance of movements involved in various loops (motif 1, 2, 3) and lips (upper and lower) in the transition of leishmanial HSK from closed to open state. Virtual screening data of more than 40,000 compounds from the present investigation tries to identify a few potential HSK inhibitors that possess important features to act as efficient HSK inhibitors. These compounds can be considered an effective starting point for the identification of novel drug-like scaffolds. We hope the structural wealth that is offered in this report will be utilized in designing competent experimental and therapeutic interventions for leishmaniasis management. Graphical abstract.