This variant has also been

This variant has also been related to a better treatment response in patients with metastatic colorectal cancer subjected to irinotecan-based chemotherapy (Kweekel et al., 2008). Inheritance of this metabolic variability has also been stated to influence better treatment outcomes in breast cancer patients (Sweeney et al., 2000). Chemical agents and environmental pollutants underlying occupational (Hemminki and Niemi, 1982, Delfino, 2002, Mapp, 2005, Clapp et al., 2006, Ahmed et al., 2007, Ziech et al., 2010, Langevin and Kelsey, 2014; Bhattacharjee and Paul, 2016), chronic (Walter et al., 2000, Sandford and Silverman, 2002, Maier, 2002, Ahmed et al., 2007, Andersen et al., 2011) as well as hereditary diseases (Wilson and Schweitzer, 1937, Scheinberg and Sternlieb, 1960, Shelby et al., 1993, Dolinoy et al., 2007, Kirkman et al., 2009, Soubry et al., 2014) have been linked with genetics (Minelli et al., 2011, Chappell et al., 2016). Individuals with specific polymorphs/variants (Hemminki et al., 1979, Bergamaschi et al., 2001, Wan et al., 2002, Song et al., 2015) in the genomic code have been recognized as being more prone to certain diseases caused by specific environmental/chemical agents. Molecular scale analysis of various genes/polymorphs that are the root cause of susceptibility to chemical pollutants, at structural and functional level have been attempted previously (Lienhart et al., 2014, Basharat et al., 2016, Munier et al., 2016). Impact of rs1695 polymorphism on enzyme stability, catalytic activity (Johansson et al., 1998, Johansson, 2002) and activity with various substrates like polyaromatic hydrocarbons, α,β-unsaturated aldehydes (Berhane and Mannervik, 1990, Berhane et al., 1994), 1,3,5-trinitrobenzene, glutathione etc. has been investigated (Prade et al., 1997, Ji et al., 1999). Ile105Val polymorphism in the GSTP1 causes differences in expression level and activity toward substrates (Johansson, 2002). Currently, no report on the dynamics simulation of the WT protein and this polymorph with chosen substrate molecules (used as drugs) exists. To find out whether binding of WT and mutated GSTP1 rs1695 polymorph with substrates, effects its conformation, binding pattern and GW 6471 profile, we have docked and simulated the apo- and holo-GSTP1 WT and rs1695 polymorphs with a nutraceutical and some FDA approved drug compounds that target GSTP1 for disease mitigation (including neuropathy and cancer).
Material and methods Structure of GSTP1 and several variants have been resolved and deposited in the Research Collaboratory for Structural Biology Protein Data Bank. The structure with ID: 3DGQ and a resolution of 1.6Å was retrieved from the database for analyses. Ile105Val variant was prepared in PyMol. RMSD calculation for WT and variant protein structure was carried out using Superpose (Maiti et al., 2004). Calculations parameters were: Similarity cut off: 2Å; Dissimilarity cut off: 3Å; Dissimilar subdomain: 7. Drugs and nutraceutical targeting GSTP1 were retrieved from the Drugbank (Table 1). These were prepared for analysis using Open Babel (O'Boyle et al., 2011). Protein structures were protonated and energy minimized before docking until a gradient of 0.05 was achieved. Molecular docking of these compounds was carried out with GSTP1 WT and variant protein in the Molecular Operating Environment (MOE) software. Docking parameters were: Placement method: Triangle matcher; First rescoring: London dG force; Top retained structures for reanalysis: 10; Refinement method: Forcefield; Second rescoring: Affinity dG; Final retained structures for analysis: 10. The final complex for analysis was chosen on the basis of least energy value S. Ligand interactions were then visualized. WT and variant protein structure were solvated using DelPhi (Li et al., 2012, Sarkar et al., 2013). Delphi is a software suite for solving the Poisson-Boltzmann equation in order to calculate electrostatic potential/energy of a biomolecule. Poisson-Boltzmann Equation is widely used implicit solvation model for calculating electrostatics in macromolecules, as it treats water a continuum solvent and is computationally more efficient. Linear solver was used for calculating Poisson-Boltzmann equation. Grid (sum of the products of electrostatic potential at each grid point and the grid charges), coulombic (energy of intramolecular electrostatic interactions in a uniform medium with the properties of the solute) and reaction field (the transfer energy of a solute from a medium with the dielectric properties of the molecule to the solution) energies were calculated using Delphi. Other parameters during energy calculations were: Forcefield: Amber; pH: 7; Exterior (solvent) dielectric constant: 80.00; Percent fill: 80.00; Grid scale: 2.00; Salt concentration: 0.10; Probe radius: 1.40; Boundary conditions: 2 (Basharat et al., 2016).