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Toxicological importance of CYP3A4 catalysis and inhibition

Award Number: R01ES025767
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2016
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Toxicological importance of CYP3A4 catalysis and inhibition - Program Director/Principal Investigator (Sevrioukova, Irina F.): Project Summary Human cytochrome P450 3A4 (CYP3A4) is the major and most clinically relevant drug-metabolizing enzyme, notoriously known for its extreme substrate promiscuity and allosteric behavior. Drugs and other xenobiotics can also stimulate and inhibit CYP3A4 activity, which frequently leads to undesired drug-drug interactions (DDIs), chemical toxicity and therapeutic failures. Despite extensive investigations, the CYP3A4 inhibitory and activation mechanisms remain incompletely understood. This proposal centers on using structural biology approaches to address key issues in both areas of CYP3A4 research. Aim 1 is set to investigate the CYP3A4 inhibitory mechanism via rational structure-based design of analogues of ritonavir, an HIV protease inhibitor whose ability to potently inhibit CYP3A4 was purely coincidental. We will identify structural determinants required for potent inhibition by rationally designing and investigating structure-activity relations of ritonavir-like compounds and, based on our findings, build a 3D-pharmacophore model for a potent CYP3A4-specific inhibitor that can be used for early prediction/elimination of the inhibitory potential in drug candidates and for development of more effective pharmacoenhancers. Aim 2 will utilize an integrated biochemical, chemical labeling, structural and computational approach to investigate the CYP3A4 substrate binding cooperativity and allosterism. Our recent structural findings confirmed the importance of the previously mapped peripheral area and identified three novel inner sites that could serve for substrate/effector docking. We will evaluate the role and relative importance of these areas by assessing how their modification/disruption affects CYP3A4 conformation, substrate binding cooperativity, stoichiometry and metabolism. The research outlined in this proposal is important from both the basic and translational science perspectives, because it will fill the knowledge gaps and provide fundamental insights into plasticity and adaptability of CYP3A4 to structurally diverse ligands, clarify molecular mechanisms underlying the complex ligand binding behavior and oxidative kinetics, and help develop better tools for in silico prediction of protein-ligand contacts, metabolic stability and DDI potential in drug candidates to improve their efficacy and reduce off-target effects. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $561,595 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Environmental Health	000	9	1/13/2025	NON-COMPETING CONTINUATION	$561,595
														Subtotal = $561,595

Issue Date FY: 2024 ( Subtotal = $561,595 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Environmental Health	000	8	1/4/2024	NON-COMPETING CONTINUATION	$561,595
														Subtotal = $561,595

Issue Date FY: 2023 ( Subtotal = $561,595 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Environmental Health	002	7	1/24/2023	NON-COMPETING CONTINUATION	$561,595
2023	2022	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Environmental Health	001	6	12/12/2022	COMPETING CONTINUATION	$59
2023	2020	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Environmental Health	000	5	12/12/2022	NON-COMPETING CONTINUATION	-$59
														Subtotal = $561,595

Issue Date FY: 2022 ( Subtotal = $561,595 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Environmental Health	001	6	2/28/2022	COMPETING CONTINUATION	$561,595
2022	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Environmental Health	000	5	2/25/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $561,595

Issue Date FY: 2020 ( Subtotal = $347,625 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Environmental Health	000	5	5/15/2020	NON-COMPETING CONTINUATION	$347,625
														Subtotal = $347,625

Issue Date FY: 2019 ( Subtotal = $347,625 )
2019	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Environmental Health	000	4	5/31/2019	NON-COMPETING CONTINUATION	$347,625
														Subtotal = $347,625

Issue Date FY: 2018 ( Subtotal = $347,625 )
2018	2018	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Environmental Health	000	3	5/30/2018	NON-COMPETING CONTINUATION	$347,625
														Subtotal = $347,625

Issue Date FY: 2017 ( Subtotal = $347,625 )
2017	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Environmental Health	000	2	5/26/2017	NON-COMPETING CONTINUATION	$347,625
														Subtotal = $347,625

Issue Date FY: 2016 ( Subtotal = $347,625 )
2016	2016	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Environmental Health	000	1	5/19/2016	NEW	$347,625
														Subtotal = $347,625

Grand Total All Awards = $3,984,505

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Toxicological importance of CYP3A4 catalysis and inhibition

Award Number: R01ES025767

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2016

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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