RESUMO
Falcipains (FPs), cysteine proteases in the malarial parasite, are emerging as the promising antimalarial drug targets. In order to identify novel FP inhibitors, we generated a pharmacophore derived from the reported co-crystal structures of inhibitors of Plasmodium falciparum Falcipain-3 to screen the ZINC library. Further, the filters were applied for dock score, drug-like characters, and clustering of similar structures. Sixteen molecules were purchased and subject to in vitro enzyme (FP-2 and FP-3) inhibition assays. Two compounds showed in vitro inhibition of FP-2 and FP-3 at low µM concentration. The selectivity of the inhibitors can be explained based on the predicted interactions of the molecule in the active site. Further, the inhibitors were evaluated in a functional assay and were found to induce morphological changes in line with their mode of action arresting Plasmodium development. Compound 15 was most potent inhibitor identified in this study.
Assuntos
Antimaláricos/farmacologia , Cisteína Endopeptidases/metabolismo , Inibidores Enzimáticos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/enzimologia , Relação Estrutura-AtividadeRESUMO
Malaria is a tropical disease with significant morbidity and mortality burden caused by Plasmodium species in Africa, the Middle East, Asia, and South America. Pathogenic Plasmodium species have lately become increasingly resistant to approved chemotherapeutics and combination therapies. Therefore, there is an emergent need for identifying new druggable targets and novel chemical classes against the parasite. Falcipains, cysteine proteases required for heme metabolism in the erythrocytic stage, have emerged as promising drug targets against Plasmodium species that infect humans. This perspective discusses the biology, biochemistry, structural features, and genetics of falcipains. The efforts to identify selective or dual inhibitors and their structure-activity relationships are reviewed to give a perspective on the design of novel compounds targeting falcipains for antimalarial activity evaluating reasons for hits and misses for this important target.