Structure-Based Design of Tetrahydroisoquinoline-Based Hydroxamic Acid Derivatives Inhibiting Human Histone Deacetylase 8

Abstract

We have designed new human histone deacetylase 8 (HDAC8) inhibitors using structure-based molecular design. 3D models of HDAC8–inhibitor complexes were prepared by in situ modification of the crystal structure of HDAC8 co-crystallized with the hydroxamic acid suberoylanilide (SAHA) and a training set (TS) of tetrahydroisoquinoline-based hydroxamic acid derivatives (DAHTs) with known inhibitory potencies. A QSAR model was elaborated for the TS yielding a linear correlation between the computed Gibbs free energies (GFE) of HDAC8–DAHTs complexation (∆∆Gcom) and observed half-maximal enzyme inhibitory concentrations (IC50exp). From this QSAR model a 3D-QSAR pharmacophore (PH4) was generated. Structural information derived from the 3D model and breakdown of computed HDAC8–DAHTs interaction energies up to individual active site residue contributions helped us to design new more potent HDAC8 inhibitors. We obtained a reasonable agreement ∆∆Gcom and values: (pIC50exp = – 0.0376 × ∆∆Gcom + 7.4605, R2 = 0.89). Similar agreement was established for the PH4 model (pIC50exp = 0.8769 × + 0.7854, R2 = 0.87). A comparative analysis of the contributions of active site residues guided the choice of fragments used in designing a virtual combinatorial library (VCL) of DAHT analogs. The VCL of more than 17 thousand DAHTs was screened by the PH4 and furnished 229 new DAHTs. The best-designed analog displayed predicted inhibitory potency up to 110 times higher than that of DAHT1 (IC50exp = 0.047 µM). Predicted pharmacokinetic profiles of the new analogs were compared to current per oral anticancer compounds. This computational approach, which combines molecular modelling, pharmacophore generation, analysis of HDAC8–DAHTs interaction energies and virtual screening of a combinatorial library of DAHTs resulted in a set of proposed new HDAC8 inhibitors. It can thus direct medicinal chemists in their search for new anticancer agents.