Molecules 2012, 17(3), 3407-3460; doi:10.3390/molecules17033407
Article

Modeling Chemical Interaction Profiles: II. Molecular Docking, Spectral Data-Activity Relationship, and Structure-Activity Relationship Models for Potent and Weak Inhibitors of Cytochrome P450 CYP3A4 Isozyme

1 Division of Toxicology and Environmental Medicine, Agency for Toxic Substances and Disease Registry, Atlanta, GA 30333, USA 2 Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA 3 Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506-9530, USA Present address: Environmental Science and Policy, ICF International, Fairfax, VA 22031, USA.
* Author to whom correspondence should be addressed.
Received: 20 January 2012; in revised form: 27 February 2012 / Accepted: 28 February 2012 / Published: 15 March 2012
(This article belongs to the Special Issue QSAR and Its Applications)
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Abstract: Polypharmacy increasingly has become a topic of public health concern, particularly as the U.S. population ages. Drug labels often contain insufficient information to enable the clinician to safely use multiple drugs. Because many of the drugs are bio-transformed by cytochrome P450 (CYP) enzymes, inhibition of CYP activity has long been associated with potentially adverse health effects. In an attempt to reduce the uncertainty pertaining to CYP-mediated drug-drug/chemical interactions, an interagency collaborative group developed a consensus approach to prioritizing information concerning CYP inhibition. The consensus involved computational molecular docking, spectral data-activity relationship (SDAR), and structure-activity relationship (SAR) models that addressed the clinical potency of CYP inhibition. The models were built upon chemicals that were categorized as either potent or weak inhibitors of the CYP3A4 isozyme. The categorization was carried out using information from clinical trials because currently available in vitro high-throughput screening data were not fully representative of the in vivo potency of inhibition. During categorization it was found that compounds, which break the Lipinski rule of five by molecular weight, were about twice more likely to be inhibitors of CYP3A4 compared to those, which obey the rule. Similarly, among inhibitors that break the rule, potent inhibitors were 2–3 times more frequent. The molecular docking classification relied on logistic regression, by which the docking scores from different docking algorithms, CYP3A4 three-dimensional structures, and binding sites on them were combined in a unified probabilistic model. The SDAR models employed a multiple linear regression approach applied to binned 1D 13C-NMR and 1D 15N-NMR spectral descriptors. Structure-based and physical-chemical descriptors were used as the basis for developing SAR models by the decision forest method. Thirty-three potent inhibitors and 88 weak inhibitors of CYP3A4 were used to train the models. Using these models, a synthetic majority rules consensus classifier was implemented, while the confidence of estimation was assigned following the percent agreement strategy. The classifier was applied to a testing set of 120 inhibitors not included in the development of the models. Five compounds of the test set, including known strong inhibitors dalfopristin and tioconazole, were classified as probable potent inhibitors of CYP3A4. Other known strong inhibitors, such as lopinavir, oltipraz, quercetin, raloxifene, and troglitazone, were among 18 compounds classified as plausible potent inhibitors of CYP3A4. The consensus estimation of inhibition potency is expected to aid in the nomination of pharmaceuticals, dietary supplements, environmental pollutants, and occupational and other chemicals for in-depth evaluation of the CYP3A4 inhibitory activity. It may serve also as an estimate of chemical interactions via CYP3A4 metabolic pharmacokinetic pathways occurring through polypharmacy and nutritional and environmental exposures to chemical mixtures.
Keywords: structure-activity relationship; SAR; QSAR; SDAR; docking; molecular modeling; inhibitor; CYP3A4; drug-drug interaction; drug-chemical interaction; DDI; DDCI

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MDPI and ACS Style

Tie, Y.; McPhail, B.; Hong, H.; Pearce, B.A.; Schnackenberg, L.K.; Ge, W.; Buzatu, D.A.; Wilkes, J.G.; Fuscoe, J.C.; Tong, W.; Fowler, B.A.; Beger, R.D.; Demchuk, E. Modeling Chemical Interaction Profiles: II. Molecular Docking, Spectral Data-Activity Relationship, and Structure-Activity Relationship Models for Potent and Weak Inhibitors of Cytochrome P450 CYP3A4 Isozyme. Molecules 2012, 17, 3407-3460.

AMA Style

Tie Y, McPhail B, Hong H, Pearce BA, Schnackenberg LK, Ge W, Buzatu DA, Wilkes JG, Fuscoe JC, Tong W, Fowler BA, Beger RD, Demchuk E. Modeling Chemical Interaction Profiles: II. Molecular Docking, Spectral Data-Activity Relationship, and Structure-Activity Relationship Models for Potent and Weak Inhibitors of Cytochrome P450 CYP3A4 Isozyme. Molecules. 2012; 17(3):3407-3460.

Chicago/Turabian Style

Tie, Yunfeng; McPhail, Brooks; Hong, Huixiao; Pearce, Bruce A.; Schnackenberg, Laura K.; Ge, Weigong; Buzatu, Dan A.; Wilkes, Jon G.; Fuscoe, James C.; Tong, Weida; Fowler, Bruce A.; Beger, Richard D.; Demchuk, Eugene. 2012. "Modeling Chemical Interaction Profiles: II. Molecular Docking, Spectral Data-Activity Relationship, and Structure-Activity Relationship Models for Potent and Weak Inhibitors of Cytochrome P450 CYP3A4 Isozyme." Molecules 17, no. 3: 3407-3460.

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