title: Searching the conformational complexity and binding properties of HDAC6 through docking and molecular dynamic simulations.
abstract: Histone deacetylases (HDACs) are a family of proteins involved in the deacetylation of histones and other non-histones substrates. HDAC6 belongs to class II and shares similar biological functions with others of its class. Nevertheless, its three-dimensional structure that involves the catalytic site remains unknown for exploring the ligand recognition properties. Therefore, in this contribution, homology modeling, 100-ns-long Molecular Dynamics (MD) simulation and docking calculations were combined to explore the conformational complexity and binding properties of the catalytic domain 2 from HDAC6 (DD2-HDAC6), for which activity and affinity toward five different ligands have been reported. Clustering analysis allowed identifying the most populated conformers present during the MD simulation, which were used as starting models to perform docking calculations with five DD2-HDAC6 inhibitors: Cay10603 (CAY), Rocilinostat (RCT), Tubastatin A (TBA), Tubacin (TBC), and Nexturastat (NXT), and then were also submitted to 100-ns-long MD simulations. Docking calculations revealed that the five inhibitors bind at the DD2-HDAC6 binding site with the lowest binding free energy, the same binding mode is maintained along the 100-ns-long MD simulations. Overall, our results provide structural information about the molecular flexibility of apo and holo DD2-HDAC6 states as well as insight of the map of interactions between DD2-HDAC6 and five well-known DD2-HDAC6 inhibitors allowing structural details to guide the drug design. Finally, we highlight the importance of combining different theoretical approaches to provide suitable structural models for structure-based drug design.
authors: a Laboratorio de Modelado Molecular y Diseño de Fármacos (Laboratory of Molecular Modeling and Drug Design), Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina , Instituto Politécnico Nacional , Mexico City 11340 , Mexico.
authors: Yudibeth
authors: Y
authors: Sixto-López
authors: a Laboratorio de Modelado Molecular y Diseño de Fármacos (Laboratory of Molecular Modeling and Drug Design), Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina , Instituto Politécnico Nacional , Mexico City 11340 , Mexico.|b Laboratorio de Biofísica y Biocatálisis, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina , Instituto Politécnico Nacional , Plan de San Luis y Salvador Díaz Mirón s/n, Casco de Santo Tomás, Ciudad de México 11340 , Mexico.
authors: Martiniano
authors: M
authors: Bello
authors: a Laboratorio de Modelado Molecular y Diseño de Fármacos (Laboratory of Molecular Modeling and Drug Design), Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina , Instituto Politécnico Nacional , Mexico City 11340 , Mexico.
authors: Rolando Alberto
authors: RA
authors: Rodríguez-Fonseca
authors: a Laboratorio de Modelado Molecular y Diseño de Fármacos (Laboratory of Molecular Modeling and Drug Design), Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina , Instituto Politécnico Nacional , Mexico City 11340 , Mexico.|b Laboratorio de Biofísica y Biocatálisis, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina , Instituto Politécnico Nacional , Plan de San Luis y Salvador Díaz Mirón s/n, Casco de Santo Tomás, Ciudad de México 11340 , Mexico.
authors: Martha Cecilia
authors: MC
authors: Rosales-Hernández
authors: a Laboratorio de Modelado Molecular y Diseño de Fármacos (Laboratory of Molecular Modeling and Drug Design), Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina , Instituto Politécnico Nacional , Mexico City 11340 , Mexico.
authors: Marlet
authors: M
authors: Martínez-Archundia
authors: c Facultad de Farmacia, Departamento de Química Farmacéutica y Orgánica , Universidad de Granada , Granada 18071 , Spain.
authors: José Antonio
authors: JA
authors: Gómez-Vidal
authors: a Laboratorio de Modelado Molecular y Diseño de Fármacos (Laboratory of Molecular Modeling and Drug Design), Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina , Instituto Politécnico Nacional , Mexico City 11340 , Mexico.
authors: José
authors: J
authors: Correa-Basurto
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000502:physiology; D020134:Catalytic Domain / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000502:physiology*; D011487:Protein Conformation; D000072417:Protein Domains / Q000502:physiology
chemical_list: D056572:Histone Deacetylase Inhibitors; D008024:Ligands; D006655:Histone Deacetylases
keywords: HDAC6; PCA; molecular dynamics simulations; molecular modeling