Advances in Computational Prediction of Regioselective and Isoform-Specific Drug Metabolism Catalyzed by CYP450s.

Abstract

Prediction of drug metabolism is an important step in the early lead optimization phase and preclinical studies. Its main purpose is to avoid late stage (Phase I–III) or post‐marketing withdrawals which usually results in a significant financial loss to a pharmaceutical company. Computational methods for identification of soft‐spots in the molecules (site of metabolism; SOM) and CYP450 isoforms responsible for drug metabolism have over the past ten years proved an indispensable tool towards achieving this goal. These methods can be broadly classified into i) ligand based, ii) structure based and iii) hybrid methods. In this review we discuss some of the most successful methods of SOM and isoform specificity prediction, their application domain, advantages, and limitations along with recent developments in the last 5 years in this area. Recent applications of molecular dynamics (MD), quantum mechanics (QM) and quantum mechanics/molecular mechanics (QM/MM) methodology for regioselective and isoform specific drug metabolism predictions are also discussed. Finally, a summary of these methods along with expected developments, future challenges and opportunities are discussed.

How Do Metal Ions Modulate the Rate‐Determining Electron‐Transfer Step in Cytochrome P450 Reactions?

“…[1,[4][5][6][7][8][9] Structure-and ligand-based models (classicala nd deep learning) predict sites of metabolism and potential isoforms with accuracies convergingt o85-90 %. [10,11] Most of the work reportedi nt he literature focused on the catalyticr oleo ft he iron(IV)-oxo heme radicalc ation species (compound I,s tructure 7 in Scheme 1)Pleaseg ive the structure of this radical cation in Scheme 1. [6,12,13] and ignoredt he fact that for the majority of the CYP450s, the rate-determining step in the catalytic cycle is the first electron transfer from CYP450 reductase (CPR), which reduces the pentacoordinated iron(III) heme (2,S cheme 1).…”

“…Understanding of the CYP450 catalytic cycle and the identity and role of reactive intermediates in the rate‐determining step has increased tremendously over the last two decades through a combination of computational and experimental efforts [1, 4–9] . Structure‐ and ligand‐based models (classical and deep learning) predict sites of metabolism and potential isoforms with accuracies converging to 85–90 % [10, 11] …”

Magnetic HMS silica as a Support to Immobilization of Catalysts Based on Cationic Manganese Porphyrins

“…Synthetic metalloporphyrins (MP) have been studied as effective catalysts for alkene epoxidation and alkane hydroxylation under mild conditions motivated by the high selectivity and efficiency presented by heme‐based biological enzymes, such as cytochrome P‐450 monooxygenases . [1–5] However, depending on the structure of the synthetic MP, their use in homogeneous systems is limited by drawbacks such as: (i) their tendency to undergo deactivation by bimolecular self‐destruction or dimerization; and (ii) the difficulty to recover them from the reaction media after the first use hampering their use in catalytic technological processes.…”

Recent advances in the prediction of non‐CYP450‐mediated drug metabolism

“…Experience in modeling metabolic outcome of CYP450-catalyzed reactions has led to the realization in the scientific community that use of combined or hybrid models is useful (sometimes necessary) for achieving high prediction accuracies. 23 Such hybrid models can make use of two or more conventional modeling methodologies (e.g., docking, QSAR, and reactivity) along with machine learning methods such as SVM, random forest, k-nearest neighbor, and others. Examples of applications of such methodologies to non-CYP450 Phase I and Phase II enzymes are rare (e.g., SOMP and XenoSite for UGT predictions).…”

“…This is only a representative list of useful tools (both free and commercial) available to the user. For an exhaustive list of softwares, research articles, and discussion on them, some of the recent reviews are highly recommended …”