AUTHOR=Lima Marilia N. N. , Cassiano Gustavo C. , Tomaz Kaira C. P. , Silva Arthur C. , Sousa Bruna K. P. , Ferreira Leticia T. , Tavella Tatyana A. , Calit Juliana , Bargieri Daniel Y. , Neves Bruno J. , Costa Fabio T. M. , Andrade Carolina Horta TITLE=Integrative Multi-Kinase Approach for the Identification of Potent Antiplasmodial Hits JOURNAL=Frontiers in Chemistry VOLUME=7 YEAR=2019 URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2019.00773 DOI=10.3389/fchem.2019.00773 ISSN=2296-2646 ABSTRACT=

Malaria is a tropical infectious disease that affects over 219 million people worldwide. Due to the constant emergence of parasitic resistance to the current antimalarial drugs, the discovery of new antimalarial drugs is a global health priority. Multi-target drug discovery is a promising and innovative strategy for drug discovery and it is currently regarded as one of the best strategies to face drug resistance. Aiming to identify new multi-target antimalarial drug candidates, we developed an integrative computational approach to select multi-kinase inhibitors for Plasmodium falciparum calcium-dependent protein kinases 1 and 4 (CDPK1 and CDPK4) and protein kinase 6 (PK6). For this purpose, we developed and validated shape-based and machine learning models to prioritize compounds for experimental evaluation. Then, we applied the best models for virtual screening of a large commercial database of drug-like molecules. Ten computational hits were experimentally evaluated against asexual blood stages of both sensitive and multi-drug resistant P. falciparum strains. Among them, LabMol-171, LabMol-172, and LabMol-181 showed potent antiplasmodial activity at nanomolar concentrations (EC50 ≤ 700 nM) and selectivity indices >15 folds. In addition, LabMol-171 and LabMol-181 showed good in vitro inhibition of P. berghei ookinete formation and therefore represent promising transmission-blocking scaffolds. Finally, docking studies with protein kinases CDPK1, CDPK4, and PK6 showed structural insights for further hit-to-lead optimization studies.