Molecular docking of chemotherapeutic agents to CYP3A4 in non-small cell lung cancer

•Chemotherapeutic drug binding to CYP3A4 was investigated.•Gemcitabine was found to have best binding affinity among the docked drugs.•Docetaxel and paclitaxel did not bind to CYP3A4*1B.•Arg 102 to be more frequently involved in drug binding to CYP3A4.•Gemcitabine + carboplatin showed best combination drug-binding affinity.

CYP3A4, a “heme” containing isoform, abundantly found in the liver, gastro-intestinal tract, lungs and renal cells, also known as drug metabolising enzyme (DME) may be responsible for the disease progression in cancers such as lung cancer. Hence, we have targeted this protein for improving drug selection and in preventing adverse reactions. The aim of this study was to examine chemotherapeutic drug binding to CYP3A4 and the interactions therein. We have used Schrödinger suite 2014, to perform molecular docking of human CYP3A4, by Induced Fit Docking using gemcitabine, cisplatin, carboplatin, docetaxel and paclitaxel drugs. We evaluated drug-binding affinities using Prime/MMGBSA and using these scores we compared the affinities of combination therapies against CYP3A4. Analysis of the docking results showed gemcitabine > carboplatin > cisplatin as the order of binding affinities, with gemcitabine having the best docking score. Interestingly, docetaxel and paclitaxel did not bind to CYP3A4*1B. The combination drug-binding affinity analysis showed gemcitabine + carboplatin to have the best docking score and hence, efficacy. Our investigation has identified the residue Arg 105 to be more frequently involved in drug binding to CYP3A4. Our results suggest that gemcitabine or combination of gemcitabine + carboplatin could serve as an excellent therapy against CYP3A4 in NSCLC patients. Thus, our study depicts binding of chemotherapeutic drugs to CYP3A4 and has identified the residues that may be targeted for therapy in NSCLC patients.

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