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In-silico identification of small molecules targeting H-Ras and in-vitro cytotoxicity with caspase-mediated apoptosis in carcinoma cells

Shah, Hetal Damani and Saranath, Dhananjaya and Das, Soma and Kharkar, Prashant and Karande, Anjali (2019) In-silico identification of small molecules targeting H-Ras and in-vitro cytotoxicity with caspase-mediated apoptosis in carcinoma cells. In: JOURNAL OF CELLULAR BIOCHEMISTRY, 120 (4). pp. 5519-5530.

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Official URL: https://doi.org/110.1002/jcb.27836


H-Ras oncogene plays a critical role in the transformation of normal cells to a malignant phenotype through constitutive activation of the GTP bound protein leading to uncontrolled cell proliferation in several human cancers. Thus, H-Ras oncoprotein serves as an excellent target for anticancer drug discovery. To identify novel H-Ras inhibitors, we performed structure-based virtual screening of the Maybridge HitFinder (TM) library using Schrodinger suite. Thirty ligands from the chemical library were identified as they showed preferential in silico binding initially to H-Ras proteins with Gly12Val, Gly13Asp, and Gly12Val-Gly13Asp mutations. Absorption, distribution, metabolism, excretion, and toxicity profile confirmed drug-like properties of the compounds. Three representative molecules were tested for antiproliferative effect on T24 urinary bladder carcinoma cell line, MCF-7 breast cancer cell line and HDF-7 normal dermal fibroblast cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Two compounds (Cmpds) showed antiproliferative activity exclusively in the cancer cell lines with minimal effect on the control HDF-7 cells. The effect of compound treatment on cell cycle progression, assessed by propidium iodide (PI) staining, depicted increased arrest of T24 cell line in the sub G1 phase. Further, Annexin-V PI dual staining and pan caspase inhibitor Z-VAD-fmk indicated caspase-dependent apoptotic activity of Cmpds 1 and 3. Our findings demonstrate caspase-dependent apoptotic activity of Cmpds 1 and 3 selectively against Gly12Val mutated T24 cancer cell line implicating a potential for treatment of bladder cancer. We envisage that these molecules may be promising candidates with potential therapeutic value in H-Ras mutation-associated cancers.

Item Type: Journal Article
Publisher: WILEY
Additional Information: Copyright of this article belongs to WILEY
Keywords: apoptosis; caspase; cell cycle analysis; H-Ras; small drug-like molecules; virtual screening
Department/Centre: Division of Biological Sciences > Biochemistry
Date Deposited: 21 Mar 2019 07:12
Last Modified: 21 Mar 2019 07:13
URI: http://eprints.iisc.ac.in/id/eprint/61919

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