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

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

  • J Biomol Struct Dyn. 2024 Jan-Feb;42(1):362-383. doi: 10.1080/07391102.2023.2192804.
Preeti Patel 1 2 Sushant Kumar Shrivastava 3 Piyoosh Sharma 3 Balak Das Kurmi 4 Ekta Shirbhate 1 Harish Rajak 1
Affiliations

Affiliations

  • 1 Medicinal Chemistry Research Laboratory, Department of Pharmacy, Guru Ghasidas University, Bilaspur, Chhattisgarh, India.
  • 2 Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab, India.
  • 3 Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, India.
  • 4 Department of Pharmaceutics, ISF College of Pharmacy, Moga, Punjab, India.
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.

Keywords

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

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-161154
    HDAC3 Inhibitor