title: A comparative study based on docking and molecular dynamics simulations over HDAC-tubulin dual inhibitors.
abstract: Nowadays the ability to prediction of complex behavior rationally based on the computational approaches has been a successful technique in drug discovery. In the present study interactions of a new series of hybrids, which were made by linking colchicine as a tubulin inhibitor and suberoylanilide hydroxamic acid (SAHA) as a HDAC inhibitor, with HDAC8 and HDAC1 were investigated and compared. This research has been facilitated by the availability of experimental information besides employing docking methodology as well as classical molecular dynamics simulations and binding free energy calculation were performed. The obtained findings indicate different modes of interactions and inhibition strengths of the studied inhibitors for HDAC8 and HDAC1. HDAC8 binding free energies (-34.35 to -26.27kcal/mol) revealed higher binding affinity to HDAC8 compared to HDAC1 (-33.17 to -7.99kcal/mol). The binding energy contribution of each residue with the hybrid compounds 4a-4e within the active site of HDAC1 and HDAC8 was analyzed and the results confirmed the rule of key amino acids in interaction with the hybrid compounds.
authors.affiliation: Department of Medicinal Chemistry & Drug Design and Development Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Malihe
authors.initials: M
authors.lastname: Hassanzadeh
authors.affiliation: Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Kowsar
authors.initials: K
authors.lastname: Bagherzadeh
authors.affiliation: Department of Medicinal Chemistry & Drug Design and Development Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: amanlou@tums.ac.ir.
authors.forename: Massoud
authors.initials: M
authors.lastname: Amanlou
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D020134:Catalytic Domain; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry*; D006655:Histone Deacetylases / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007477:Ions; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015203:Reproducibility of Results; D013816:Thermodynamics; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry
chemical_list: D000596:Amino Acids; D056572:Histone Deacetylase Inhibitors; D007477:Ions; D008024:Ligands; D014404:Tubulin; D050257:Tubulin Modulators; D006655:Histone Deacetylases; D015032:Zinc
keywords: Docking; Free binding energy; Histone deacetylase 1; Histone deacetylase 8; Hybrid ligands; Molecular dynamics simulations