title: Computational design of a time-dependent histone deacetylase 2 selective inhibitor.
abstract: Development of isoform-selective histone deacetylase (HDAC) inhibitors is of great biological and medical interest. Among 11 zinc-dependent HDAC isoforms, it is particularly challenging to achieve isoform inhibition selectivity between HDAC1 and HDAC2 due to their very high structural similarities. In this work, by developing and applying a novel de novo reaction-mechanism-based inhibitor design strategy to exploit the reactivity difference, we have discovered the first HDAC2-selective inhibitor, β-hydroxymethyl chalcone. Our bioassay experiments show that this new compound has a unique time-dependent selective inhibition on HDAC2, leading to about 20-fold isoform-selectivity against HDAC1. Furthermore, our ab initio QM/MM molecular dynamics simulations, a state-of-the-art approach to study reactions in biological systems, have elucidated how the β-hydroxymethyl chalcone can achieve the distinct time-dependent inhibition toward HDAC2.
authors.affiliation: †School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Zhou
authors.affiliation: †School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: †School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China.
authors.forename: Nanhao
authors.initials: N
authors.lastname: Chen
authors.affiliation: ‡Department of Chemistry, New York University, New York, New York 10003, United States.
authors.forename: Shenglong
authors.initials: S
authors.lastname: Wang
authors.affiliation: †School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China.
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Luo
authors.affiliation: ‡Department of Chemistry, New York University, New York, New York 10003, United States.|§NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai 200062, P.R. China.
authors.forename: Yingkai
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: †School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China.
authors.forename: Ruibo
authors.initials: R
authors.lastname: Wu
mesh_terms: D001665:Binding Sites; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry*; D017076:Computer-Aided Design; D015195:Drug Design; D055808:Drug Discovery; D056284:Histone Deacetylase 1 / Q000737:chemistry*; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D013997:Time Factors
chemical_list: D047188:Chalcones; D056572:Histone Deacetylase Inhibitors; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2