Electrostatic potential along with measurement

Electrostatic potential along with measurement and modeling of corresponding energies is vital for inferring protein properties, lone or complexed with ligands. DelPhi was used for solving Poisson Boltzmann equation, obtaining grid, total reaction and coulombic energies after solvating the proteins and their complexes. Solvent was treated as a continuum medium with high dielectric constant. Biomolecules were taken as low dielectric cavities comprised of charged atoms. Extreme variation was observed in coulombic CC-223 profile for busulfan binding with WT and variant polymorph (Fig. 1). Decrement in binding energy was also observed for the WT and variant polymorph calculated with MOE (Table 2). GSTP1 gene has demonstrated 18% of busulfan conjugation activity (Czerwinski et al., 1996). Reduced enzyme activity due to Ile105Val GSTP1 polymorphism might lead to variability in pharmacokinetics of busulfan drug in patients. No significant role of Ile105Val in busulfan exposures and reduction could be inferred in pharmacogenetic studies on pediatric (Johnson et al., 2008, Zwaveling et al., 2008a, Zwaveling et al., 2008b, Ansari et al., 2010, Ansari et al., 2013) and adult patients (Ten Brink et al., 2012) undergoing hematopoetic stem cell transplantation, but this variant was associated with lower enzyme activity and increased busulfan exposure in a cohort of Arab children suffering from congenital hemoglobinopathies and undergoing hematopoietic stem cell transplantation (Elhasid et al., 2010). Bremer et al. reported that Ile105Val is associated with lower enzyme activity and increased busulfan exposure (Bremer et al., 2015). The reported associations between the variant, drug exposure, and clinical outcome suggest a potential for genotype-guided busulfan dosing. Inconsistency in results calls for more studies focused on GSTP1 variant association with busulfan treatment in larger patient datasets from varying ethnicities to confirm or refute the results (Goekkurt et al., 2007, Zwaveling et al., 2008a, Zwaveling et al., 2008b) and could improve our knowledge on role of SNPs in drug safety/toxicity and efficacy. Our findings complement that Ile105Val polymorpshism leads to varied busulfan binding and energy profile of a SNP bound drug is different from that of WT bound drug/substrate. It also sheds light on the varied energy profile of the variant bound ligand/drug and helps infer changes even in those cases where the differences are minute or overshadowed by other factors, establishing importance of informatics as a quick and handy method to infer changes in SNPs vs WT substrate binding. All other compounds also showed energy differences in energy landscape for WT and Ile105Val polymorph bound compound complexes (Supplementary Table 1). A major increase in total grid energy was observed for all variant polymorphs complexed with compound except with carboplatin which showed a reverse trend. Differences ranged from around 500Kt to order of thousands. Studies have reported significant association of GSTP1 Ile105Val polymorphism with response to carboplatin-based chemotherapy. Patients with the variant allele respond better to platinum-based (in this case carboplatin-based) chemotherapy, compared to the ones having WT gene as reported for ovarian cancer (Kim et al., 2009, Sawers et al., 2014), colorectal cancer (Stoehlmacher et al., 2002, Stoehlmacher et al., 2004) and advanced non-small cell lung cancer patients (Sun et al., 2010, Zhou et al., 2011). In some studies, GSTP1 Ile105Val polymorph showed no effect on treatment response as in non-small cell lung cancer (Pillot et al., 2006) and ovarian cancer (Marsh et al., 2007, Zhai et al., 2016). One of the reasons quoted for better response to carboplatin in patients with variant genotype is that since GSTP1 is crucial to proper cell function and detoxification, individuals with variant GSTP1 genotypes show increased susceptibility to cancer and diseases but favourable response to chemotherapy as decreased clearance of chemotherapeutic agents could prove beneficial. Although some studies have indicated GSTP1 as a predictive marker for clinical outcome in patients treated with platinum-based chemotherapy but overall, the results show inconsistency and larger population datasets are required for further verification. Possible reason for insignificant variation in binding GSTP1 WT and SNP with carboplatin could be due to multiple factors but our analysis led to the conclusion that computational approach is a swift method to deduce changes in binding and energy parameters of drug bound SNP and WT protein, even in those cases having trivial effect or superseded by other parameters.