Discovery and evaluation of new trypanocydal compounds by in silico drug repositioning

SBARAGLINI, MARIA LAURA; ALBA SOTO, CATALINA D.; RUIZ, MARÍA D.; CARRILLO, CAROLINA; ALBERCA, LUCAS NICOLÁS; MORALES, JUAN FRANCISCO; TALEVI, ALAN

Santiago

Congreso; XXIV Congreso Latinoamericano de Parasitología.; 2017

Introduction: Chagas disease, sleeping sickness and leishmaniasis belong to the group of neglected tropicaldiseases. Despite the increasing knowledge on the biology of trypanosomatids, available medications stillshow safety issues and, in some cases, limited efficacy. It is hence necessary to find new treatments that canovercome the limitations of the currently approved drugs. Drug repositioning involves finding newtherapeutic indications for approved, discontinued or investigational drugs. This strategy has remarkableadvantages over the search for de novo drugs since the new indication is built on the already availablepharmacokinetic and safety knowledge of the repurposed drug. N-myristoyl transferase catalyzes the transferof myristate from myristoyl coenzyme A to the glycine residue of the protein target. This enzyme has beengenetically and biochemically validated as a molecular target for Trypanosoma brucei, Trypanosoma cruziand Leishmania spp. Objetive: Finding approved drugs that inhibit NMT of trypanosomatides.Methodology: We have compiled a database of compounds tested against NMT of T. brucei. From this, wehave generated and validated computational models capable of discriminating between ?inhibitors? and ?noninhibitors?of the NMT. The best models were combined and applied to the in silico screening of Drug Bank3.0 and Sweetlead databases. The best 500 compounds were subjected to an additional filter by determiningthe applicability domain. Additionally, we have determined the probability that each compound will be activeusing surface plots of Positivity Predictive Values. Based on these results, costs and accessibility, three ofthese drugs were purchased for in vitro evaluation. Results: The three tested drugs showed a strongtrypanocidal activity on T. cruzi epimastigotes (EC50 < 5 µM), and a moderate inhibitory activity against T.cruzi trypomastigotes. Conclusion: The results show the importance of computer-guided drug repositioningsince we have found trypanocidal compounds with a minimal investment of time and resources.University of La Plata, CONICET, PICT 2013-0520.