Pharmacophoric studies of in vitro inhibition of Plasmodium falciparum growth.

Malaria continues to be a scourge in India and the situation has been compounded by the emergence of resistant strains of Plasmodium falciparum which is the primary cause of fatality in this disease. Therefore, there is an urgent need to develop newer drugs. Molecular modeling and pharmacophoric determination have become predominant methods today in the design and synthesis of newer and more effective drugs. Many Plasmodium specific enzymes and proteins involved in crucial biochemical pathways have been identified and their structures have been determined by X-ray crystallography. These enzymes and proteins are excellent targets for newer antimalarial agents. Bisphosphonates have shown potent inhibitory activity against Plasmodium farneysl diphosphate synthase (FPPS) enzyme, which is vital to the protein prenylation pathway of the organism. In this study, a set of 26 bisphosphonate inhibitors, synthesized by Oldfield et al [J Med Chem (2008) 51, 7827-7833] were subjected to rigorous 3D-QSAR studies using the PHASE computational package. In vitro Plasmodium growth inhibition rather than direct enzyme inhibition was considered in the study for a more realistic approach. Good statistical correlations were obtained for the pharmacophoric model as revealed by the regression values, indicating good stability of the model. Three hydrogen bond acceptors and a hydrogen bond donor defined the pharmacophore from the present study. This pharmacophore, AAAD (A = Hydrogen bond acceptor and D = Hydrogen bond donor) was put through a search-run for matching structures from the SPECS database yielding four matching structures, which could function as starting points for more novel and potent antimalarials.