In silico identification of novel competitive and alosteric inhibitors of falcipains 2 and 3

Abstract

Malaria is a devastating infectious disease caused by parasites of the genus Plasmodia. Nearly half of the world's population, lives in areas where malaria is endemic and roughly one million deaths in children are reported every year. During the first decade of this century a dozen or so new drugs entered the clinical development and also new ways of accelerating the discovery of antimalarials have arisen. However, emerging drug resistance represents a tremendous challenge for the eradication of malaria. Under the current situation, the development of new antimalarials is urgently needed, as well as the concomitant search for new drug targets. In this sense, the food vacuole proteases involved in hemoglobin degradation during the intraerythrocytic stage of the parasite's life cycle have been described as promising drug targets. Among this group of proteases, the cysteine proteases falcipain 2 (FP-2) and falcipain 3 (FP-3), considered as a key hemoglobinases, have been extensively targeted for the development of novel antimalarials. To date, most works, however, have focused on the identification of competitive inhibitors against both enzymes and none has explored the allosteric inhibition, which was demonstrated for FP-2 in recent years. Our project will be devoted, then, to the identification of both competitive and allosteric inhibitors of FP-2 and FP-3 through an integrated in silico and experimental approach. We will combined state-of-the-art molecular modeling tools, such as docking, MD simulations, free energy and cross-correlation analysis to provide structural information on the binding modes of the inhibitors identified in our work, as well as a structural and energetic explanation of the allosteric modulation of FP-2 and, presumably, of FP-3. We expect to provide a framework to exploit the allosteric modulation of FPs, and its potential towards the design of more specific drugs.