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

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.

Quantitative activity-activity relationship (QAAR) driven design to develop hydroxamate derivatives of pentanoic acids as selective HDAC8 inhibitors: Synthesis, biological evaluation and binding mode of interaction studies

Histone deacetylase 8 (HDAC8) has been implicated as a potential drug target of many disease including cancer. HDAC8 isoform selectivity over other class-I HDACs is a major concern now-a-days. In...

Discovery of novel potential selective HDAC8 inhibitors by combine ligand-based, structure-based virtual screening and in-vitro biological evaluation

Neuroblastoma is the most common extracranial solid tumor found in children and survival rate is extremely meager. HDAC8, a class I zinc-dependent enzyme, is a potential drug target for treatment of neuroblastoma and T cell lymphoma. Most of the HDAC8 inhibitors discovered till date contains a hydroxamic acid group which acts as a zinc binding group. The high binding affinity to the zinc and other ions results in adverse effects. Also, the non-selective inhibition of HDACs cause a variety of side effects. The objective of this is to identify structurally diverse, non-hydroxamate, novel, potential and selective HDAC8 inhibitors. A number of five featured pharmacophore hypotheses were generated using 32 known selective HDAC8 inhibitors. The hypotheses ADDRR.4 were selected for building 3D QSAR model. This model has an excellent correlation coefficient and good predictive ability, which was employed for virtual screening of Phase database containing 4.3 × 106 molecules. The resultant hits with fitness score >1.0 were optimized using in-silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) and XP glide docking studies. On the basis of pharmacophore matching, interacting amino acid residues, XP glide score, more affinity towards HDAC8 and less affinity towards other HDACs, and ADME results five hits- SD-01, SD-02, SD-03, SD-04 and SD-05 with new structural scaffolds, non-hydroxamate were selected for in vitro activity study. SD-01 and SD-02 were found to be active in the nanomolar (nM) range. SD-01 had considerably good selectivity for HDAC8 over HDAC6 and SD-02 had marginal selectivity for HDAC6 over HDAC8. The compounds SD-01 and SD-02 were found to inhibit HDAC8 at concentrations (IC50) 9.0 nM and 2.7 nM, respectively.