title: Building a three-dimensional model of CYP2C9 inhibition using the Autocorrelator: an autonomous model generator.
abstract: In modern day drug discovery campaigns, computational chemists have to be concerned not only about improving the potency of molecules but also reducing any off-target ADMET activity. There are a plethora of antitargets that computational chemists may have to consider. Fortunately many antitargets have crystal structures deposited in the PDB. These structures are immediately useful to our Autocorrelator: an automated model generator that optimizes variables for building computational models. This paper describes the use of the Autocorrelator to construct high quality docking models for cytochrome P450 2C9 (CYP2C9) from two publicly available crystal structures. Both models result in strong correlation coefficients (R² > 0.66) between the predicted and experimental determined log(IC₅₀) values. Results from the two models overlap well with each other, converging on the same scoring function, deprotonated charge state, and predicted the binding orientation for our collection of molecules.
authors.affiliation: Anadys Pharmaceuticals, Inc., San Diego, CA, USA. matthew.lardy@takedasd.com
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Lardy
authors.forename: Laurie
authors.initials: L
authors.lastname: Lebrun
authors.forename: Drew
authors.initials: D
authors.lastname: Bullard
authors.forename: Charles
authors.initials: C
authors.lastname: Kissinger
authors.forename: Alberto
authors.initials: A
authors.lastname: Gobbi
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D003198:Computer Simulation; D065729:Cytochrome P-450 CYP2C9; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005480:Flurbiprofen / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D014859:Warfarin / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D005480:Flurbiprofen; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases