Author(s): Neelima Arora, Amit Kumar Banerjee, Upadhyayula Surya Narayana Mur
Malaria remains one of the leading causes of deaths attributable to a communicable disease globally. The reemergence of drug-resistant Plasmodium falciparum, the most fatal human malarial parasite, has necessitated the exploration of different pathways to provide the urgently required novel drug targets. Aspartate carbamoyltransferase, an enzyme of de novo pyrimidine biosynthetic pathway in Plasmodium represents an attractive drug target. The enzyme was characterized using in silico tools. Tertiary (3D) structure of the enzyme was generated using the structure of Aspartate carbamoyltransferase of Pyrococcus abyssi (PDB ID: 1ML4) as template by comparative modeling and validated by various structural quality validation tools. The model was stable during the simulation with the equilibrium root-mean-square standard deviation value of ~1 Å. Results from structure assessment tools indicated the reasonably good quality of model. Several inhibitor molecules were docked in the active site of the modeled protein for determining the binding affinity of these molecules toward the protein. Out of various inhibitors used in the study, 3-(4-Hydroxy-phenyl)-2-(2-phosphono-acetylamino)-propionic acid showed highest binding affinity towards ACT. This study provides new insights towards understanding the 3-D Pf ACT structure and binding affinity of selected inhibitor compounds and also paves a way for designing novel anti-malarials.