Computer-guided drug repurposing: Identification of trypanocidal activity of clofazimine, benidipine and saquinavir

BELLERA C ; BALCAZAR D ; VANRELL M ; CASASSA M ; PALESTRO P ; GAVERNET L ; LABRIOLA C ; GALVEZ J ; BRUNO BLANCH L ; ROMANO P ; CARRILLO C ; TALEVI A

Buenos Aires

Congreso; Sociedad Argentina de Protozoología; 2014

Sociedad Argentina de Protozoología

Cruzipain (Cz) is the main cystein protease of Trypanosoma cruzi and has previously been validated s new drug target, proving to be essential for replication of the intracellular form of T. cruzi and playing a role in host-parasite interactions. We present an integrative approach for the search of novel antichagasic agents, including virtual screening (VS) of Cz inhibitors oriented to knowledge-based drug repositioning, and subsequent biochemical, cellular and pre-clinical testing. A computational classificatory model capable of discriminating between Cz inhibitors and non-inhibitors was obtained using DESMOL11software (Molecular Topology & Drug Design Unit. University of Valencia,Spain) and Statistica 10 (statsoft 2010). Such model was validated and applied in the VS of Merck Index 12th. 154 compounds were selected as promising candidate, 34 correspond to approved drugs, which are the most favourable, direct candidates for repositioning purposes, four of which were tested in enzymatic assays and epimastigote cultures. Three of them (clofazimine, benidipine and saquinavir) showed clear inhibitory effects on Cz and antiproliferative effects on T. cruzi.) Based on pharmacological criteria, clofazimine and benidipine were moved to preclinical stage, where they were effective in a mice model of acute infection. Clofazimine also reduced the allocation of T. cruzi nests in cardiac tissue, suggesting it could be useful to prevent the development of cardiac damage in people suffering Chagas. The present work successfully integrates computer-aided drug discovery with molecular and cellular biology and preclinical testing, confirming the utility of VS to develop knowledge-based drug repurposing.