Hernandez-Gonzalez, Jorge E.
Hernandez Ramirez, Luisa F.
Pascual, Maria J.
Alvarez, Diego E.
Leite, Vitor B. P.
Pascutti, Pedro G.
Valiente, Pedro A.
Total Authors: 9
 Univ Estadual Paulista, Dept Fis, UNESP, BR-15054000 Sao Paulo - Brazil
 Univ Havana, Fac Biol, Ctr Prot Studies, Computat Biol & Biomol Dynam Lab, Havana - Cuba
 Univ Nacl San Martin UNSAM, IIB INTECH, Inst Invest Biotecnol, Inst Tecnol Chascomus, CONICET, Buenos Aires, DF - Argentina
 Univ Antioquia, Fac Med, Grp Malaria, Medellin - Colombia
 Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Dinam & Modelagem Mol, Ave Carlos Chagas Filho, 373 CCS Bloco D Sala 30, BR-21941902 Rio De Janeiro - Brazil
Total Affiliations: 5
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS;
Web of Science Citations:
Background: Falcipain 2 (FP-2) is the hemoglobin-degrading cysteine protease of Plasmodium falciparum most extensively targeted to develop novel antimalarials. However, no commercial antimalarial drugs based on FP-2 inhibition are available yet due to the low selectivity of most FP-2 inhibitors against the human cysteine pro teases. Methods: A structure-based virtual screening (SVBS) using Maybridge HitFinderr (TM) compound database was conducted to identify potential FP-2 inhibitors. In vitro enzymatic and cell-growth inhibition assays were performed for the top-scoring compounds. Docking, molecular dynamics (MD) simulations and free energy calculations were employed to study the interaction of the best hits with FP-2 and other related enzymes. Results and conclusions: Two hits based on 4-(9H-fluoren-9-yl) piperazin-1-yl) methanone scaffold, HTS07940 and HTS08262, were identified as inhibitors of FP-2 (half-maximal inhibitory concentration (IC50) = 64 mu M and 14.7 mu M, respectively) without a detectable inhibition against the human off-target cathepsin K (hCatK). HTS07940 and HTS08262 inhibited the growth of the multidrug-resistant P. falciparum strain FCR3 in culture (half-maximal inhibitory concentrations (IC50) = 2.91 mu M and 34 mu M, respectively) and exhibited only moderate cytotoxicity against HeLa cells (Half-maximal cytotoxic concentration (CC50) = 133 M mu and 350 mu M, respectively). Free energy calculations reproduced the experimental affinities of the hits for FP-2 and explained the selectivity with respect to hCatK. General significance: To the best of our knowledge, HTS07940 stands among the most selective FP-2 inhibitors identified by SBVS reported so far, displaying moderate antiplasmodial activity and low cytotoxicity against human cells. Hence, this compound constitutes a promising lead for the design of more potent and selective FP-2 inhibitors. (AU)