Plasmodium vivax 1-deoxy-D-xylulose-5-phosphate synthase: HomologyModeling, Domain Swapping,and Virtual Screening

Abstract

Structure-based computational approaches are needed to model proteins in the absence of any crystal structures and identify protein-ligand interactions. Biochemical pathways that exist in microorganisms but absent in humans serve as excellent targets for antimicrobial drug design. The Non-Mevalonate Pathway (NMP) is one such pathway that is present in all intra-erythrocytic stages of Plasmodium and could serve as a target for anti-malarial drug design and development. The first enzyme of the pathway, DXS (1-deoxy-D-xylulose-5-phosphate synthase) is the rate limiting enzyme and is also important for the biosynthesis of pyridoxal and thiamine. In the absence of available crystal structures, our aim was to develop homology models for Plasmodium DXS, which could provide insight into the structural features of this enzyme and its likely binding to ligands. Initial models were built using the PRIME module of Schrödinger Suite 2010 and then refined using MacroModel energy minimization. Analyses were also carried out using bioinformatics tools to predict domain swapping in Plasmodium DXS. This study should prove useful in the design and development of novel anti-malarial therapeutics.