Determination of binding mode of 1, 3, 4- thiadazole on cytochrome p450 2b4: a virtual screening and molecular docking study

The human genome encodes more than fifty-seven functional Cytochrome P450 proteins and mainly five isomers (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) account for 90% of drug metabolism. This accounting changes from the liver to intestinal and other extra-hepatic organs. Most are found on the endoplasmic reticulum of eukaryotic cells, but few are localized primarily in mitochondria. The majority of these are involved in metabolism for biotransformation of many drugs, environmental pollutants, steroids, fatty acids, bile acids, fat soluble vitamins as well as in activation of several carcinogens. Cytochrome P450 isomers are a super family of HEME protein enzymes which differ in their substrate specificity. They are influenced by numerous factors including age, sex, nutrition as well as exposure to certain CYP inducers. The HEME iron catalyzes cleavage of O-O bond leaving an iron linked oxygen atom that provides potent oxidant. The special features of CYP family of enzymes are ability to metabolize multiple substrates which differ in size, shape and stereochemistry. 1, 3, 4 Thiadiazole and its derivatives represents one of the most biological active classes of compound possessing a wide spectrum of activities. Literature survey shows that the 1,3,4 Thiadiazole nucleus is associated with diverse pharmacological activities such as antifungal, antibacterial, anti- inflammatory, anticancer, anti-tubercular, antiviral and anti-parkinsonism. We have attempted with the help of Virtual Screening and Molecular Docking approach to study the binding mode of 1,3,4 Thiadiazole on Cytochrome P450. A study of around 3500 derivatives has been conducted and the binding energies were in the range of -9.13 kcal/mol to -2.63 kcal/mol. As of structure analysis 20 molecules showed better binding affinities with the active site Thr302. Our study gives an idea about the interaction between the active site residues and the substrate which is explained on the basis of size & hydrophobicity of the binding pocket. The study provides hints for future design of drugs with higher potency and specificity.