The metabolism of drugs and other xenobiotics by cytochrome P450 enzymes (CYP) is an essential detoxification and drug clearance mechanism in humans. Despite the publication of several X-ray structures since 2000, reliable computational prediction of drug metabolism remains a huge challenge. In this grant application, we propose an integrative high-throughput approach that combines electronic properties of a ligand with structural properties of the protein. Our main aim is the development and application of innovative structure-based design techniques that address serious shortcomings of current approaches. In particular, we have extended our novel docking concept to incorporate all observed forms of protein flexibility relevant for ligand-CYP interactions, entropic contributions influencing the prediction of binding poses, and we will add on- the-fly solvation to ligand-CYP complexes. To improve the docking quality we will optimize the parameters of a scoring function tailor-made for each CYP enzyme studied. In combination with an initial focus on efficient calculation of hydrogen-abstraction energies we will predict regioselective metabolism of drugs or drug candidates binding to CYPs. Based on the resulting docking poses, multidimensional QSAR simulations will be performed for accurate quantification of binding affinity as a measure CYP-inhibition and better ranking of binding modes. The new computational methods will be applied to two CYP enzymes (CYP2C9, 3A4) important in drug metabolism. The generated computational models will be stored in a database and made publicly available. Other researchers will be invited to screen compounds against our CYP database via a secure Web protocol to predict drug metabolism and inhibition. The submission of data by other researchers will provide valuable feedback on the performance and applicability of the models.

Public Health Relevance

Cytochrome P450 mediated drug metabolism plays a critical role for the efficacy of administered drugs. This project is aimed toward developing and applying innovative computational methods to efficiently predict drug metabolism as well as inhibition of the drug metabolizing enzymes. The resulting computational models allow for the estimation of drug efficiency and the potential of adverse reactions early in drug discovery and thus have a strong impact on drug development.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-DKUS-F (02))
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Okita, Richard T
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Purdue University
Schools of Pharmacy
West Lafayette
United States
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Yang, Ying; Lill, Markus A (2016) Dissecting the Influence of Protein Flexibility on the Location and Thermodynamic Profile of Explicit Water Molecules in Protein-Ligand Binding. J Chem Theory Comput 12:4578-92
Kingsley, Laura J; Esquivel-Rodríguez, Juan; Yang, Ying et al. (2016) Ranking protein-protein docking results using steered molecular dynamics and potential of mean force calculations. J Comput Chem 37:1861-5
Kingsley, Laura J; Wilson, Gregory L; Essex, Morgan E et al. (2015) Combining structure- and ligand-based approaches to improve site of metabolism prediction in CYP2C9 substrates. Pharm Res 32:986-1001
Kingsley, Laura J; Lill, Markus A (2015) Substrate tunnels in enzymes: structure-function relationships and computational methodology. Proteins 83:599-611
Hu, Bingjie; Lill, Markus A (2014) WATsite: hydration site prediction program with PyMOL interface. J Comput Chem 35:1255-60
Kingsley, Laura J; Lill, Markus A (2014) Ensemble generation and the influence of protein flexibility on geometric tunnel prediction in cytochrome P450 enzymes. PLoS One 9:e99408
Kingsley, Laura J; Lill, Markus A (2014) Including ligand-induced protein flexibility into protein tunnel prediction. J Comput Chem 35:1748-56
Yang, Ying; Hu, Bingjie; Lill, Markus A (2014) Analysis of factors influencing hydration site prediction based on molecular dynamics simulations. J Chem Inf Model 54:2987-95
Hu, Bingjie; Lill, Markus A (2014) PharmDock: a pharmacophore-based docking program. J Cheminform 6:14
Xu, Mengang; Lill, Markus A (2013) Induced fit docking, and the use of QM/MM methods in docking. Drug Discov Today Technol 10:e411-8

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