Identification of (4-(9H-fluoren-9-yl) piperazin-1-yl) methanone derivatives as falcipain 2 inhibitors active against Plasmodium falciparum cultures

ABSTRACT: 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 proteases. Methods: A structure-based virtual screening (SVBS) using Maybridge HitFinder™ 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 μM and 14.7 μM, 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 μM and 34 μM, respectively) and exhibited only moderate cytotoxicity against HeLa cells (Half-maximal cytotoxic concentration (CC50) = 133 μM and 350 μM, 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.

• Autores: Hernández González, Jorge Enrique; Salas Sarduy, Emir; Hernández Ramírez, Luisa Fernanda; Pascual, María José; Álvarez, Diego; Pabón Vidal, Adriana; Leitea, Vitor Barbanti; Pascuttie, Pedro; Valiente, Pedro
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2018
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/26424
• Acceso en línea: http://hdl.handle.net/10495/26424
• Palabra clave: Plasmodium falciparum; Simulación de Dinámica Molecular; Molecular Dynamics Simulation; Antimaláricos; Antimalarials; Cisteína Endopeptidasas; Cysteine Endopeptidases; Concentración 50 Inhibidora; Inhibitory Concentration 50; Relación Estructura-Actividad; Structure-Activity Relationship
• Rights: openAccess
• License: http://purl.org/coar/access_right/c_abf2