In Silico Three Dimensional Pharmacophore Models to Aid the Discovery and Design of New Antimalarial Agents

Apurba   K.   Bhattacharjee

Abstract

Malaria is one of the most dangerous diseases affecting primarily poor people of tropical and subtropical regions of the world with a worldwide death toll of over 1.5 million a year coupled with increasing resistance to common antimalarial drugs, such as chloroquine and mefloquine, justifies WHOs appeal for search and delivery of novel antimalarial drugs as quick as possible. This review describes how by using in silico (computational) methods, specifically three-dimensional QSAR pharmacophores developed from known antimalarial compounds could be used as screening tools for identification of potential new candidates through search of virtual compound libraries. The review is based on two select examples of pharmacophore models published by us recently: the antimalarial indolo[2,1-b]quinazoline-6,12-diones (tryptanthrins) and the tricyclic antidepressants as chloroquine (CQ) resistance reversal agents. The model developed from the tryptanthrins was found to correlate well with this class of compounds and predictive for other known antimalarials of different chemical classes, such as quinolines, chalcones, rhodamine dyes, Pfmrk (malarial cyclin dependent kinase inhibitors), malarial FabH (KASIII) inhibitors, and plasmepsin inhibitors. Similarly, the CQ-resistance reversal model too is found to be fairly well correlated for the tricyclic antidepressants and predictive for a variety of other known CQ-resistance reversal agents. The pharmacophores allowed search and identification of potent antimalarial compounds from in-house databases and enabled custom designed synthesis of new potent analogues.

Keywords: Drug discovery, Tryptanthrins, antimalarial activity, pharmacophore development, cyclin dependent protein kinase (CDK) inhibitors

« Previous Next »