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

ALBERCA L.N.; SBARAGLINI, M.L.; RUIZ, M.D.; MORALES J.F.; ALBA SOTO C.; CARRILLO C.; TALEVI A.

Santiago

Congreso; XXIV Congreso Latinoamericano de Parasitología; 2017

Sociedad Chilena de Parasitología (SOCHIPA)

Chagas disease, sleeping sickness and leishmaniasis belong to the group of neglected tropical diseases. Despite the increasing knowledge on the biology of trypanosomatids, available medications still show safety issues and, in some cases, limited efficacy. It is hence necessary to find new treatments that can overcome the limitations of the currently approved drugs. Drug repositioning involves finding new therapeutic indications for approved, discontinued or investigational drugs. This strategy has remarkable advantages over the search for de novo drugs since the new indication is built on the already available pharmacokinetic and safety knowledge of the repurposed drug. N-myristoyl transferase catalyzes the transfer of myristate from myristoyl coenzyme A to the glycine residue of the protein target. This enzyme has been genetically and biochemically validated as a molecular target for Trypanosoma brucei, Trypanosoma cruzi and 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, we have generated and validated computational models capable of discriminating between ?inhibitors? and ?non-inhibitors? of the NMT. The best models were combined and applied to the in silico screening of Drug Bank 3.0 and Sweetlead databases. The best 500 compounds were subjected to an additional filter by determining the applicability domain. Additionally, we have determined the probability that each compound will be active using surface plots of Positivity Predictive Values. Based on these results, costs and accessibility, three of these drugs were purchased for in vitro evaluation. Results: The three tested drugs showed a strong trypanocidal 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 repositioning since we have found trypanocidal compounds with a minimal investment of time and resources.