Hydroxamic acid derivatives as selective HDAC3 inhibitors: computer-aided drug design strategies

Abstract

Histone deacetylases (HDACs) are critical epigenetic drug targets that have gained significant attention in the scientific community for the treatment of cancer. The currently marketed HDAC inhibitors lack selectivity for the various HDAC isoenzymes. Here, we describe our protocol for the discovery of novel potential hydroxamic acid based HDAC3 inhibitors through pharmacophore modeling, virtual screening, docking, molecular dynamics (MD) simulation and toxicity studies. The ten pharmacophore hypotheses were established, and their reliability was validated by different ROC (receiving operator curve) analysis. Among them, the best model (Hypothesis 9 or RRRA) was employed for searching SCHEMBL, ZINC and MolPort database to screen out hit molecules as selective HDAC3 inhibitors, followed by different docking stages. MD simulation (50 ns) and MMGBSA study were performed to study the stability of ligand binding modes and with the help of trajectory analysis, to calculate the ligand-receptor complex RMSD (root-mean-square deviation), RMSF (root-mean-square fluctuation) and H-bond distance, etc. Finally, in-silico toxicity studies were performed on top screened molecules and compared with reference drug SAHA and established structure-activity relationship (SAR). The results indicated that compound 31, with high inhibitory potency and less toxicity (probability value 0.418), is suitable for further experimental analysis.

Communicated by Ramaswamy H. Sarma

HIGHLIGHTS

• Pharmacophore modeling and virtual screening were performed with hydroxamic acid derivatives as HDAC3 inhibitors.

• MD simulation was performed for 50 ns time duration for selected protein-ligand complexes.

• SAR and toxicity studies (using TOPKAT tool) were performed.

• The results of these studies might be valuable in the further design and development of more potent HDAC3 inhibitors.

Keywords:

• HDAC3 inhibitor
• Hydroxamic acid
• MD simulation
• Discovery studio
• Structure-activity relationship
• TOPKAT

Acknowledgments

Preeti Patel and Balak Das Kurmi are thankful to ICMR New Delhi, India for providing financial assistance in the form of ICMR ‘Adhoc’ Research Project (2021-10799-F1). Harish Rajak is grateful to ICMR, New Delhi, India for providing financial support in the form of an Extra-Mural Research project to Dr. Harish Rajak (58/33/2020/PHA/BMS).

Disclosure statement

The authors declare that they have no conflict of interest.

Additional information

Funding

Preeti Patel and Balak Das Kurmi is thankful to ICMR New Delhi, India for providing financial assistance in the form of ICMR “Adhoc” Research Project (2021-10799-F1). Harish Rajak is grateful to ICMR, New Delhi, India for providing financial support in the form of an Extra-Mural Research project to Dr. Harish Rajak (58/33/2020/PHA/BMS).