Ligand-Based Site of Metabolism Prediction for Cytochrome P450 2D6

Abstract

A ligand-based method based on the SMARTCyp approach that predicts the sites of cytochrome P450 2D6-mediated metabolism of druglike molecules has been developed. The method uses only two descriptors besides the reactivity from SMARTCyp: the distance to a protonated nitrogen atom and the distance to the end of the molecule. Hence, the site of metabolism is predicted directly from the 2D structure of a molecule, without requiring calculation of electronic properties or generation of 3D structures. Testing on an independent test set gives an area under the curve value of 0.94, and a site of metabolism is found among the top two ranked atoms for 91% of the compounds. KEYWORDS: CYP2D6, cytochrome P450, drug metabolism C ytochrome P450 (CYP) constitutes an ubiquitous family of enzymes, and from a drug perspective, its most important function is to metabolize drug compounds. In the development of drugs, it is important at an early stage to be able to identify the site of metabolism (SOM) of the lead compounds to be able to guide the development of compounds with a desirable pharmacokinetic profile.The CYP 3A4 isoform is the most important enzyme in the degradation of drug compounds and metabolize about 50% of them. CYP 3A4 is promiscuous and is capable of converting both small and large compounds, and crystal structures have shown that the volume of the active site can change dramatically upon binding of ligands. 1−3 This is probably also why it is possible to use ligand-based models to predict how a druglike compound is metabolized for CYP 3A4, because binding in this flexible pocket is not too restrictive, and thus, the intrinsic reactivity plays a significant role. For example, it was possible with the SMARTCyp method, 4,5 which primarily takes the intrinsic reactivity into account, to predict a SOM within the top two ranked atoms for 81% of the compounds within a set of 361 druglike compounds. 5 The second most drug-metabolizing CYP enzyme, the 2D6 isoform, is more selective in its recognition of the substrates. Generally, many medium-sized amines are metabolized, however, not many of them by N-dealkylation of amines but rather further away from this functional group. The crystal structure of CYP 2D6 reveals that a there are two negatively charged amino acids in the upper part of the binding cavity of 2D6, that is, Glu216 and Asp301, which may facilitate the binding of the positively charged parts of the substrates. 6 The fact that the enzyme induces the binding suggests that it is relevant to use the protein structures to predict how drug compounds are metabolized. This is probably why only few studies of pure ligand-based models on SOM prediction for CYP2D6 exist, 7 and structural information of protein has been included for these purposes. de Groot and co-workers combined structural models of CYP2D6 and pharmacophore modeling with AM1 energies of intermediates and products to predict the SOMs. 8,9 Later studies have shown the importance of including water molecules and using ensembles of protein struct...

RS-Predictor Models Augmented with SMARTCyp Reactivities: Robust Metabolic Regioselectivity Predictions for Nine CYP Isozymes

“…SMARTCyp(V1.5) has not been calibrated towards any specific isoform, though post-submission a separate 2D6 SMARTCyp model has been released. 37 At the time of publication, neither StarDrop nor Schrödinger possess 1A2, 2A6, 2B6, 2C19, 2C8 or 2E1 regioselectivity models.…”

Pharmacokinetic optimitzation of CCG-203971: Novel inhibitors of the Rho/MRTF/SRF transcriptional pathway as potential antifibrotic therapeutics for systemic scleroderma

“…An analysis by SMARTCyp 15–16 predicted that the primary sites for metabolism are the furan (a known structural alert 17 ) and the 5-carbon of the piperidine-3-carboxylic acid. Metabolite id experiments on several analogs indicated oxidation of the piperidine ring and the left-hand aromatic ring as well as hydrolysis of the secondary carboxamide as major pathways (Supplemental).…”

Prediction of reacting atoms for the major biotransformation reactions of organic xenobiotics

“…Top-1, Top-2, Top-3 are metrics by which a molecule is considered to be correctly predicted if any experimental reacting atom is ranked as first, first or second, or first, second or third, respectively [26]. …”