Vitamin D receptor (VDR) non-synonymous single nucleotide polymorphisms (nsSNPs) affect the calcitriol drug response...

Pharmacogenetics and pharmacogenomics have become presumptive with advancements in next-generation sequencing technology. In complex diseases, distinguishing the feasibility of pathogenic and neutral disease-causing variants is a time consuming and expensive process. Recent drug research and development processes mainly rely on the relationship between the genotype and phenotype through Single nucleotide polymorphisms (SNPs). The SNPs play an indispensable role in elucidating the individual's vulnerability to disease and drug response. The understanding of the interplay between these leads to the establishment of personalized medicine. In order to address this issue, we developed a computational pipeline of vitamin D receptor (VDR) for SNP centered study by application of elegant molecular docking and molecular dynamics simulation approaches. In a few SNPs the volume of the binding cavities has increased in mutant structures when compared to the wild type, indicating a weakening in interaction (699.1 ų in wild type Vs. 738.8 in Leu230Val, 820.7 ų in Arg247Leu). This also differently reflected in the H-bond interactions and binding free energies -169.93 kcal/mol (wild type) Vs -156.43 kcal/mol (R154W), -105.49 kcal/mol (R274L) in Leu230Val and Arg247Leu respectively. Although we could not find noteworthy changes in the binding free energies and binding pocket in the remaining mutations, the H-bond interactions made these SNPs deleterious. Thus, we further analyzed the H-bond interactions and distances using molecular dynamics (MD) simulation studies.