×
The submission system is temporarily under maintenance. Please send your manuscripts to
Go to Editorial ManagerVital cellular processes such as, proliferation and tumor progression were reported to be centrally controlled by histone deacetylase (HDAC) enzymes which make them an interesting therapeutic target. Recently, a new paradigm has attracted researches to combine nonsteroidal anti-inflammatory drugs (NSAIDs) with para-aminobenzoic acid (PABA) and a zinc binding group (ZBG), presenting a synergistic impact on HDAC activity and inflammatory process. In the current study, a novel series of hybrid compounds (A1-6) were designed and evaluated for their HDAC binding affinity by molecular docking technique along with conducting an in-silico ADME (absorption, distribution, metabolism, and elimination) profiling to assess their pharmacokinetic characteristics. Compound A6 displayed the highest binding energy score (-9.539 kcal/mol) with the active site of HDAC 8 enzyme compared with the reference ligand, SAHA (-4.606 kcal/mol). Its worth mentioning that compound A6 has comparable coordination to the catalytic zinc ion with SAHA along with engaging additional hydrophobic and aromatic interaction within the active site of HDAC 8 enzyme. ADME analysis predicated high gastrointestinal absorption for A2, A5, and A6, which also comply with Lipinski's rule, indicating good oral bioavailability. Conversely, A1, A3, and A4 showed moderate absorption, suitable for parenteral or localized/colon-targeted delivery, potentially advantageous for colon cancer treatment. These results highlight these hybrids’ potential as HDAC inhibitors and support further synthesis and biological testing.
Objective: Histone deacetylase-2 (HDAC-2) has emerged as an important molecular target in cancer therapy because of its role in gene silencing, regulation of the cell cycle, and resistance to apoptosis in several cancer types. In the present study, a series of novel 4-aminoantipyrine-based derivatives incorporating semicarbazide, thiosemicarbazide, and hydroxylamine pharmacophoric groups were rationally designed and evaluated for their potential HDAC-2 inhibitory activity using in silico approaches. Methods:. The binding affinity of the newly designed compounds toward the HDAC-2 enzyme and their interactions within the catalytic pocket were investigated using molecular docking analysis. The three-dimensional structure of HDAC-2 (PDB ID: 4LXZ) was obtained from the RCSB Protein Data Bank and prepared for docking studies. Results: Docking indicated that ligand stability within the enzyme active site was mainly achieved through coordination with the catalytic zinc ion, in addition to hydrogen bonding and hydrophobic interactions with essential amino acid residues located in the HDAC-2 catalytic domain. The reference inhibitor vorinostat (SAHA) was used as a standard compound and produced a docking score of −5.445 kcal/mol. Among the designed compounds, Compound Ia exhibited the most favorable binding energy with a calculated ΔG of −9.711 kcal/mol. In addition, Compound IIe and Compound Ib demonstrated promising docking scores of −8.285 and −8.147 kcal/mol, respectively. Conclusions: Pharmacokinetic properties were predicted using the QikProp module, revealing that most designed compounds exhibited acceptable drug-likeness according to Lipinski’s Rule of Five. These computational findings suggest that the designed derivatives may represent promising candidates as HDAC-2 inhibitors with potential anticancer activity.