Virtual screening for novel 1-deoxy-D-xylulose-5-phosphate reductoisomerase inhibitors: A shape-based search approach

Abstract

A virtual screening study using the ArgusDock docking engine, implemented in ArgusLab 4.0.1 was performed on 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), the second enzyme in the methylerythritol phosphate pathway, in isoprenoid production, which is present in the malarial parasite Plasmodium falciparum. This enzyme has been proven to be the molecular target for fosmidomycin, a promising antimalarial drug. However, fosmidomycin exhibits poor pharmacokinetic properties and has low intestinal absorption. In this study, a subset of the ZINC12 database composed of 7,478 molecules was docked on DXR (PDB ID: 5JO0) using the ArgusDock (a shape-based search algorithm), to find a hit that correlated with the fosmidomycin analogs. This shape-based search algorithm was chosen, to virtually screen a large database on a computer, due to its fast docking capability. The screened compounds’ outputs were ZINC00310125, ZINC17111658, and ZINC59231267. These three compounds possessed the required ligand-enzyme interactions, as shown in fosmidomycin analog 1. In conclusion, the shape-based search algorithm implemented in ArgusLab 4.0.1 was found to be a relatively easy alternate method of performing virtual screening using a 3D database. The method could be used to develop novel antimalarial drugs.