Insights on Cytochrome P450 Enzymes and Inhibitors Obtained Through QSAR Studies

The cytochrome P450 (CYP) superfamily of heme enzymes play an important role in the metabolism of a large number of endogenous and exogenous compounds, including most of the drugs currently on the market. Inhibitors of CYP enzymes have important roles in the treatment of several disease conditions such as numerous cancers and fungal infections in addition to their critical role in drug-drug interactions. Structure activity relationships (SAR), and three-dimensional quantitative structure activity relationships (3D-QSAR) represent important tools in understanding the interactions of the inhibitors with the active sites of the CYP enzymes. A comprehensive account of the QSAR studies on the major human CYPs 1A1, 1A2, 1B1, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 and a few other CYPs are detailed in this review which will provide us with an insight into the individual/common characteristics of the active sites of these enzymes and the enzyme-inhibitor interactions.

[1]  S. Free,et al.  A MATHEMATICAL CONTRIBUTION TO STRUCTURE-ACTIVITY STUDIES. , 1964, Journal of medicinal chemistry.

[2]  C. Hansch,et al.  p-σ-π Analysis. A Method for the Correlation of Biological Activity and Chemical Structure , 1964 .

[3]  C. Hansch.  Quantitative approach to biochemical structure-activity relationships , 1969 .

[4]  G. Cohen,et al.  Involvement of a hydrophobic site in the inhibition of the microsomal p-hydroxylation of aniline by alcohols. , 1973, Molecular pharmacology.

[5]  R. Cramer,et al.  Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. , 1988, Journal of the American Chemical Society.

[6]  D. Mansuy,et al.  The substrate binding site of human liver cytochrome P450 2C9: an approach using designed tienilic acid derivatives and molecular modeling. , 1995, Biochemistry.

[7]  D. Wade,et al.  Probing the active sites of rat and human cytochrome P450 2E1 with alcohols and carboxylic acids. , 1995, Archives of biochemistry and biophysics.

[8]  Jeffrey P. Jones,et al.  Three-dimensional quantitative structure-activity relationship for inhibitors of cytochrome P4502C9. , 1996, Drug metabolism and disposition: the biological fate of chemicals.

[9]  J A McKay,et al.  Tumor-specific expression of cytochrome P450 CYP1B1. , 1997, Cancer research.

[10]  J. Gasteiger,et al.  Knowledge Discovery in Reaction Databases: Landscaping Organic Reactions by a Self-Organizing Neural Network , 1997 .

[11]  E. Bowman,et al.  Characterisation of xenobiotic-metabolising enzyme expression in human bronchial mucosa and peripheral lung tissues. , 1998, European journal of cancer.

[12]  G I Murray,et al.  The role of cytochrome P450 in tumour development and progression and its potential in therapy , 2000, The Journal of pathology.

[13]  Jeffrey P. Jones,et al.  A refined 3-dimensional QSAR of cytochrome P450 2C9: computational predictions of drug interactions. , 2000, Journal of medicinal chemistry.

[14]  S. Ekins,et al.  Three- and four-dimensional-quantitative structure activity relationship (3D/4D-QSAR) analyses of CYP2C9 inhibitors. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[15]  T. Shimada,et al.  Metabolic activation of polycyclic aromatic hydrocarbons and other procarcinogens by cytochromes P450 1A1 and P450 1B1 allelic variants and other human cytochromes P450 in Salmonella typhimurium NM2009. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[16]  S. Ekins,et al.  Pharmacophore and three-dimensional quantitative structure activity relationship methods for modeling cytochrome p450 active sites. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[17]  F. Gonzalez,et al.  The use of gene knockout mice to unravel the mechanisms of toxicity and chemical carcinogenesis. , 2001, Toxicology letters.

[18]  David F. V. Lewis,et al.  Structure–activity relationship for human cytochrome P450 substrates and inhibitors , 2002, Drug metabolism reviews.

[19]  D. Lewis.  Modelling human cytochrome P450-substrate interactions. , 2002, Ernst Schering Research Foundation workshop.

[20]  H. Kubinyi.  Comparative Molecular Field Analysis (CoMFA) , 2002 .

[21]  W. Trager,et al.  (+)-N-3-Benzyl-nirvanol and (-)-N-3-benzyl-phenobarbital: new potent and selective in vitro inhibitors of CYP2C19. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[22]  Alexandre Arenas,et al.  An Integrated SOM-Fuzzy ARTMAP Neural System for the Evaluation of Toxicity , 2002, J. Chem. Inf. Comput. Sci..

[23]  E. Offord,et al.  In vitro investigation of cytochrome P450-mediated metabolism of dietary flavonoids. , 2002, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[24]  Alexandre Arenas,et al.  Fuzzy ARTMAP and Back-Propagation Neural Networks Based Quantitative Structure-Property Relationships (QSPRs) for Octanol-Water Partition Coefficient of Organic Compounds , 2002, J. Chem. Inf. Comput. Sci..

[25]  S. Imaoka,et al.  Involvement of CYP2J2 and CYP4F12 in the metabolism of ebastine in human intestinal microsomes. , 2002, The Journal of pharmacology and experimental therapeutics.

[26]  D. Lewis,et al.  Molecular Binding Interactions: Their Estimation and Rationalization in QSARs in Terms of Theoretically Derived Parameters , 2002, TheScientificWorldJournal.

[27]  Maurice Dickins,et al.  Substrate SARs in human P450s. , 2002, Drug discovery today.

[28]  I. Pajeva,et al.  Quantitative structure-activity relationship (QSAR) and three-dimensional QSAR analysis of a series of xanthates as inhibitors and inactivators of cytochrome P450 2B1 , 2002, Xenobiotica; the fate of foreign compounds in biological systems.

[29]  David F. V. Lewis,et al.  Molecular modeling of human cytochrome P450–substrate interactions , 2002, Drug metabolism reviews.

[30]  B G Lake,et al.  Quantitative structure--activity relationships for inducers of cytochromes P450 and nuclear receptor ligands involved in P450 regulation within the CYP1, CYP2, CYP3 and CYP4 families. , 2002, Toxicology.

[31]  Darko Butina,et al.  Modeling Aqueous Solubility , 2003, J. Chem. Inf. Comput. Sci..

[32]  J. Double,et al.  Cytochrome P450 1B1 (CYP1B1) is overexpressed in human colon adenocarcinomas relative to normal colon: implications for drug development. , 2003, Molecular cancer therapeutics.

[33]  Ralph Kühne,et al.  Stepwise discrimination between four modes of toxic action of phenols in the Tetrahymena pyriformis assay. , 2003, Chemical research in toxicology.

[34]  Jeffrey P. Jones,et al.  Active-site characteristics of CYP2C19 and CYP2C9 probed with hydantoin and barbiturate inhibitors. , 2004, Archives of biochemistry and biophysics.

[35]  G. Murray,et al.  Cytochrome P450 enzymes: novel options for cancer therapeutics. , 2004, Molecular cancer therapeutics.

[36]  David F. V. Lewis,et al.  Quantitative structure–activity relationships (QSARs) within the cytochrome P450 system: QSARs describing substrate binding, inhibition and induction of P450s , 2004, InflammoPharmacology.

[37]  Jeffrey P. Jones,et al.  Quantitative binding models for CYP2C9 based on benzbromarone analogues. , 2004, Biochemistry.

[38]  L. Maltais,et al.  Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. , 2004, Pharmacogenetics.

[39]  G. Murray,et al.  Cytochrome P450 enzymes and tumor therapy. , 2004, Molecular cancer therapeutics.

[40]  Fumiyoshi Yamashita,et al.  In silico approaches for predicting ADME properties of drugs. , 2004, Drug metabolism and pharmacokinetics.

[41]  Akbar Nayeem,et al.  A 3D-QSAR model for CYP2D6 inhibition in the aryloxypropanolamine series. , 2005, Bioorganic & medicinal chemistry letters.

[42]  Antti Poso,et al.  Predictive three-dimensional quantitative structure-activity relationship of cytochrome P450 1A2 inhibitors. , 2005, Journal of medicinal chemistry.

[43]  M. Ramos,et al.  Theoretical quantitative structure-activity relationships of flavone ligands interacting with cytochrome P450 1A1 and 1A2 isozymes. , 2005, Bioorganic & medicinal chemistry.

[44]  R. Dahiya,et al.  Cytochrome P450 1B1 Is Overexpressed and Regulated by Hypomethylation in Prostate Cancer , 2005, Clinical Cancer Research.

[45]  C. Locuson,et al.  THREE-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS OF CYTOCHROMES P450: EFFECT OF INCORPORATING HIGHER-AFFINITY LIGANDS AND POTENTIAL NEW APPLICATIONS , 2005, Drug Metabolism and Disposition.

[46]  Antti Poso,et al.  Quantitative structure-activity relationship analysis of inhibitors of the nicotine metabolizing CYP2A6 enzyme. , 2005, Journal of medicinal chemistry.

[47]  Xiaodong Zhang,et al.  5-substituted, 6-substituted, and unsubstituted 3-heteroaromatic pyridine analogues of nicotine as selective inhibitors of cytochrome P-450 2A6. , 2005, Journal of medicinal chemistry.

[48]  D. Lewis,et al.  Lipophilicity Relationships in Inhibitors of CYP2C9 and CYP2C19 Enzymes , 2006, Journal of enzyme inhibition and medicinal chemistry.

[49]  Wei Shi,et al.  QSAR Modeling of in Vitro Inhibition of Cytochrome P450 3A4 , 2006, J. Chem. Inf. Model..

[50]  M Ingelman-Sundberg,et al.  Cytochrome P450 pharmacogenetics and cancer , 2006, Oncogene.

[51]  A. Bosserhoff,et al.  Systematic search for gastric cancer-specific genes based on SAGE data: melanoma inhibitory activity and matrix metalloproteinase-10 are novel prognostic factors in patients with gastric cancer , 2006, Oncogene.

[52]  D. Nebert,et al.  The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis , 2006, Nature Reviews Cancer.

[53]  M. Ingelman-Sundberg,et al.  Tumor-specific expression of the novel cytochrome P450 enzyme, CYP2W1. , 2006, Biochemical and biophysical research communications.

[54]  D. Lewis,et al.  Quantitative structure-activity relationships (QSARs) in inhibitors of various cytochromes P450: The importance of compound lipophilicity , 2007, Journal of enzyme inhibition and medicinal chemistry.

[55]  R. D. Bruno,et al.  Targeting cytochrome P450 enzymes: a new approach in anti-cancer drug development. , 2007, Bioorganic & medicinal chemistry.

[56]  Scott Boyer,et al.  Generation of in-silico cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A4 inhibition QSAR models , 2007, J. Comput. Aided Mol. Des..

[57]  O Pelkonen,et al.  New potent and selective cytochrome P450 2B6 (CYP2B6) inhibitors based on three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) analysis , 2007, British journal of pharmacology.

[58]  Advances in the interpretation and prediction of CYP2E1 metabolism from a biochemical perspective. , 2008, Expert opinion on drug metabolism & toxicology.

[59]  Kunal Roy,et al.  Comparative QSAR Studies of CYP1A2 Inhibitor Flavonoids Using 2D and 3D Descriptors , 2008, Chemical biology & drug design.

[60]  O Pelkonen,et al.  Identification of inhibitors of the nicotine metabolising CYP2A6 enzyme—an in silico approach , 2008, The Pharmacogenomics Journal.

[61]  Yongjun Wang,et al.  Considerations and recent advances in QSAR models for cytochrome P450-mediated drug metabolism prediction , 2008, J. Comput. Aided Mol. Des..

[62]  E. Stone,et al.  Synthesis and biological properties of benzothiazole, benzoxazole, and chromen-4-one analogues of the potent antitumor agent 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (PMX 610, NSC 721648). , 2008, Journal of medicinal chemistry.

[63]  G. Lushington,et al.  Key Residues Controlling Binding of Diverse Ligands to Human Cytochrome P450 2A Enzymes , 2009, Drug Metabolism and Disposition.

[64]  Kunal Roy,et al.  Comparative chemometric modeling of cytochrome 3A4 inhibitory activity of structurally diverse compounds using stepwise MLR, FA-MLR, PLS, GFA, G/PLS and ANN techniques. , 2009, European journal of medicinal chemistry.

[65]  Kunal Roy,et al.  QSAR Studies of CYP2D6 Inhibitor Aryloxypropanolamines Using 2D and 3D Descriptors , 2009, Chemical biology & drug design.

[66]  Kunal Roy,et al.  QSAR of cytochrome inhibitors , 2009, Expert opinion on drug metabolism & toxicology.

[67]  Han Chang,et al.  Overexpression of cytochrome P450 1B1 in advanced non-small cell lung cancer: a potential therapeutic target. , 2009, Anticancer research.

[68]  Patrick Bultinck,et al.  Conceptual DFT properties‐based 3D QSAR: Analysis of inhibitors of the nicotine metabolizing CYP2A6 enzyme , 2009, J. Comput. Chem..

[69]  Christoph Helma,et al.  Classification of cytochrome p(450) activities using machine learning methods. , 2009, Molecular pharmaceutics.

[70]  Olivier Taboureau,et al.  Classification of Cytochrome P450 1A2 Inhibitors and Noninhibitors by Machine Learning Techniques , 2009, Drug Metabolism and Disposition.

[71]  Yan Li,et al.  Insight into the effects of chiral isomers quinidine and quinine on CYP2D6 inhibition. , 2009, Bioorganic & medicinal chemistry letters.

[72]  P. Roy,et al.  Exploring QSAR and QAAR for inhibitors of cytochrome P450 2A6 and 2A5 enzymes using GFA and G/PLS techniques. , 2009, European journal of medicinal chemistry.

[73]  J. Sridhar,et al.  In silico studies of polyaromatic hydrocarbon inhibitors of cytochrome P450 enzymes 1A1, 1A2, 2A6, and 2B1. , 2010, Chemical research in toxicology.

[74]  P. Roy,et al.  Pharmacophore mapping, molecular docking and QSAR studies of structurally diverse compounds as CYP2B6 inhibitors , 2010 .

[75]  D. Lewis,et al.  Quantitative structure-activity relationships (QSARs) for inhibitors and substrates of CYP2B enzymes: importance of compound lipophilicity in explanation of potency differences , 2010, Journal of Enzyme Inhibition and Medicinal Chemistry.

[76]  Remigijus Didziapetris,et al.  Trainable structure–activity relationship model for virtual screening of CYP3A4 inhibition , 2010, J. Comput. Aided Mol. Des..

[77]  Gen-Yan Liu,et al.  CoMFA and molecular docking studies of benzoxazoles and benzothiazoles as CYP450 1A1 inhibitors. , 2010, European journal of medicinal chemistry.

[78]  Igor V Tetko,et al.  A comparison of different QSAR approaches to modeling CYP450 1A2 inhibition , 2011, J. Chem. Inf. Model..

[79]  J. Leppänen,et al.  Identification of novel CYP2A6 inhibitors by virtual screening. , 2011, Bioorganic & medicinal chemistry.

[80]  S. Gharaghani,et al.  Docking, molecular dynamics simulation studies, and structure-based QSAR model on cytochrome P450 2A6 inhibitors , 2012, Structural Chemistry.

[81]  J. Sridhar,et al.  QSAR models of cytochrome P450 enzyme 1A2 inhibitors using CoMFA, CoMSIA and HQSAR , 2011, SAR and QSAR in environmental research.

[82]  T. Shimada,et al.  Docking and QSAR comparative studies of polycyclic aromatic hydrocarbons and other procarcinogen interactions with cytochromes P450 1A1 and 1B1 , 2012, SAR and QSAR in environmental research.

[83]  E. B. Wedebye,et al.  Identification of cytochrome P450 2D6 and 2C9 substrates and inhibitors by QSAR analysis. , 2012, Bioorganic & medicinal chemistry.

[84]  J. Sridhar,et al.  Development of flavone propargyl ethers as potent and selective inhibitors of cytochrome P450 enzymes 1A1 and 1A2. , 2013, Drug metabolism letters.