Discovery of Inhibitors of Tgf-�?�? Type I Receptor Using Qsar, Pharmacophore Modelling and Toxicity Assessment Techniques/Study to Target Cancer

Ajay Kumar TV; Kabilan S; Parthasarathy V

Abstract

Discovery of Inhibitors of Tgf-�?�? Type I Receptor Using Qsar, Pharmacophore Modelling and Toxicity Assessment Techniques/Study to Target Cancer

Author(s): Ajay Kumar TV, Kabilan S, Parthasarathy V

Targeting of the proteins is the current approach to discover new small molecule inhibitors. The protein TGF β type I receptor has been used as a target to identify the potential compounds. Around 64 hit compounds from binding database, were identified for 3D-QSAR study. The Schrodinger “PHASE” was used to perform the pharmacophore generation and through validation a best pharmacophore has been identified. The features of the pharmacophore were utilized to screen the molecules from National Cancer Institute (NCI) and Zinc database. Using screening techniques, about 5033 molecules were identified and the entire molecules were docked using “GLIDE” to the protein TGF β type I (PDBID: 1VJY). After the successful docking 25 hit molecules were further filtered and screened for ADME properties studies using QikProp tool. About 9 lead molecules preferred and their toxicity parameters evaluated using the softwares namely, OSIRIS property explorer, in silico-first, Molinspiration and Toxtree. The molecular properties such as clogS, clogP and Molecular weight were predicted by means of Molinspiration software as well as the drug-likeness and drug score using the OSIRIS property explorer. The other toxicity parameters such as, mutagenic, tumorigenic, irritant and reproductive effective were predicted using data warrior software. In silico first software tool was used to predict the teratogenicity of the entire compounds. About nine compounds tested for its toxicity to Salmonella. typhimurium TA100 mutagen, eye irritation as well as corrosion. In addition to these, skin sensitation alerts, negative for genotoxic carcinogenicity and non genotoxic carcinogenicity were also calculated. Using the results the compound 5 also known as Zinc-84409571 was found as a better molecule and safe to use as a drug. Hence, the compound could be further redesigned, synthesized to target cancer.

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