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Predicting drug-target interaction in cancers using homology modeled structures of MTHFR gene

Ch KK, Jamil K, Raju GS

Pharmacogenomics uses bioinformatics tools to study how an individual��?s genetic makeup affects the body��?s response to drugs. Our aim was towards the understanding of the possible role of structural variations in breast cancer drug metabolising gene such as MTHFR that closely interact with the neoplastic drugs viz. Cyclophosphamide, 5-Fluorouracil, Methotrexate and others. We investigated the polymorphism in the gene that might affect the drug binding capacity of these molecules. We used VEGA genome browser for obtaining information about the gene��?structure and dbSNPs of NCBI for SNPs. The Protein sequence was retrieved from NCBI database and using Swiss Homology method the protein structure was constructed. Linux based software TRITON was used to study and determine the mutations in the structure. For predicting the variations of drug binding capacities of the chemotherapeutic agents, we used Molegro Virtual Docker. This study revealed that the binding energy for mutated MTHFR structures of the proteins was greater than that of the wild type proteins. This indicates that mutations causing structural modifications modulated the drug binding energies with various ligands (drugs). It therefore shows that the variations in the structure of the proteins influences the drug-binding capacity and also influences drug toxicity related to drug-gene interactions. This is the first computational report for these drug-gene interactions. This study determined the pharmaco-genomic interactions in chemotherapeutic drugs commonly used for breast cancer. This could be a model study for drug designing or selecting a drug suitable to the individual patient��?s genomic response.