# Cytochrome P-450 Polymorphism

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $799,695

## Abstract

Cytochrome P450 monooxygenases often determine the clearance of candidate drugs limiting their therapeutic
efficacy. These enzymes can also be sources of off-target toxicity. Our long term objective is to understand
the structural determinants of substrate recognition by P450 enzymes. Collectively and individually the human
drug metabolizing P450s can metabolize structurally diverse range of substrates, and this is likely to reflect in
part the flexibility of each enzyme and structural adaptations for substrate binding. This underscores the
necessity to determine multiple structures of individual enzymes in complex with structurally dissimilar drugs to
understand the contribution of conformational flexibility to drug binding. Specific changes in the active site
architectures of P450s 1A2, 2C19 and 3A5 induced by interaction with chemically diverse substrates or
inhibitors will be identified to delineate the range of adaptive changes that can occur for each enzyme.
Additionally, the active site topologies of P450s 2J2, 3A7 and representative family 4A enzymes will also be
determined to identify structural characteristics that control the important functional contribution made by these
enzymes to drug metabolism and to the clearance of xenobiotics and excess endogenous compounds.
Collectively, these studies will address significant gaps in our knowledge of P450 structure as it relates to
function, and provide important information and tools for lead compound optimization in drug development to
improve efficacy and reduce risks of metabolic drug-drug interactions.

## Key facts

- **NIH application ID:** 10214627
- **Project number:** 5R01GM031001-40
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** ERIC F JOHNSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $799,695
- **Award type:** 5
- **Project period:** 1982-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10214627

## Citation

> US National Institutes of Health, RePORTER application 10214627, Cytochrome P-450 Polymorphism (5R01GM031001-40). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10214627. Licensed CC0.

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