Nikum D. Sitwala

Bio: Nikum D. Sitwala is an academic researcher from Nirma University of Science and Technology. The author has contributed to research in topics: Docking (molecular) & Benzimidazole. The author has an hindex of 3, co-authored 5 publications receiving 19 citations.

Pharmacophore modelling, validation, 3D virtual screening, docking, design and in silico ADMET simulation study of histone deacetylase class-1 inhibitors

Abstract: Histone deacetylase class-1 (HDAC class-1) over expression plays an important role during the carcinogenesis by inducing epigenetic silence of tumour suppressor genes. Thus, HDAC class-1 inhibitors have emerged as the promising therapeutic agents for multiple human cancers, since they can obstruct the activity of specific HDACs, restore the expression of some tumour suppressor genes and induce cell differentiation, growth arrest and apoptosis. Validated pharmacophore modelling along with molecular docking study is described here as a rational approach for the development of novel active hits. Pharmacophore model was generated using DISCOtech module and refined by genetic algorithm similarity programme, taking various active inhibitors in the IC50 range of 0.02–72 nM. The best pharmacophore model was validated with receiver operating curve method and Guner–Henry scoring method followed by 3D virtual screening. Several compounds with different structures (scaffolds) were retrieved as hits. After applying the drug likeliness filtering, molecules with the highest Q fit values and a known inhibitor were docked in the catalytic domain site of HDAC class-1 for further exploration of the binding mode of these compounds. Finally, in silico pharmacokinetic and toxicities were predicted for active hit molecules which are referred as potential HDAC class-1 inhibitors. Finally, four ligands are designed which fulfil the pharmacophoric requirement and can be further developed as potent hits.

3D QSAR-based design and liquid phase combinatorial synthesis of 1,2-disubstituted benzimidazole-5-carboxylic acid and 3-substituted-5H-benzimidazo[1,2-d][1,4]benzodiazepin-6(7H)-one derivatives as anti-mycobacterial agents.

Abstract: Tuberculosis (TB) is one of the world's deadliest infectious diseases, caused by Mycobacterium tuberculosis (Mtb). In the present study, a 3D QSAR study was performed for the design of novel substituted benzimidazole derivatives as anti-mycobacterial agents. The anti-tubercular activity of the designed compounds was predicted using the generated 3D QSAR models. The designed compounds which showed better activity were synthesized as 1,2-disubstituted benzimidazole-5-carboxylic acid derivatives (series 1) and 3-substituted-5H-benzimidazo[1,2-d][1,4]benzodiazepin-6(7H)-one derivatives (series 2) using the liquid phase combinatorial approach using a soluble polymer assisted support (PEG5000). The compounds were characterized by 1H-NMR, 13C-NMR, FTIR and mass spectrometry. HPLC analysis was carried out to evaluate the purity of the compounds. We observed that the synthesised compounds inhibited the growth of intracellular M. tuberculosis H37Rv in a bactericidal manner. The most active compound 16 displayed an MIC value of 0.0975 μM against the Mtb H37Rv strain in liquid cultures. The lead compound was also able to inhibit the growth of intracellular mycobacteria in THP-1 macrophages.