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Next-generation alchemical free energy methods and quantum/machine-learning models for drug discovery

Award Number: R01GM107485
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2015
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Next-generation alchemical free energy methods and quantum/machine-learning models for drug discovery - Next-generation alchemical free energy methods and quantum/machine-learning models for drug discovery. PI: Darrin M. York, Rutgers University, Piscataway, NJ 08854-8087 USA. Alchemical free energy (AFE) simulations are indispensable in various aspects of drug discovery by enabling the prediction of ligand binding afﬁnity and selectivity. A critical barrier to progress is the current limitation in pre- cision and accuracy of AFE simulations that restricts their predictive capability. The current proposal addresses these barriers with new AFE methods and models that will be integrated into the GPU-accelerated AMBER soft- ware suite used worldwide (over 30K users) in academia, government labs and industry. Speciﬁcally, we propose to: 1. Create advanced technology for robust high-precision AFE simulations; 2. Develop accurate quantum mechanical/deep-learning potential (QDπ) force ﬁelds for drug discovery and 3. Validate precision and accu- racy of AFE methods and QDπ model. In Aim 1, we will develop new technologies for robust and reproducible calculation of ligand-protein binding free energies of compound libraries. The methods work together to enable highly precise, converged AFE simulations across thermodynamic graph networks. In Aim 2, we will develop a highly accurate and computationally efﬁcient general quantum deep-potential interaction (QDπ) force ﬁeld model for drug discovery. The QDπ model will be formulated as a machine learning potential correction (∆-MLP) to the quantum mechanical/molecular mechanical (QM/MM) energy using fast, approximate 3rd-order density-functional tight-binding QM model and well-established AMBER MM force ﬁelds and compatible water and ions models. The ∆-MLP will leverage our recently developed range-corrected deep-learning potential (DPRc) for accurate intra- and intermolecular interactions. In Aim 3, we will conduct in depth validation studies of the AFE methods from Aim 1 and QDπ model of Aim 2 on a systematic set of benchmark systems, including macrophage migration inhibitory factor (MIF), JAK2 JH2 domain, SARS-Cov2 Mpro, and sigma 1 and 2 receptors.


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 = $325,881 )
2025	2025	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	11	8/19/2025	NON-COMPETING CONTINUATION	$325,881
														Subtotal = $325,881

Issue Date FY: 2024 ( Subtotal = $325,881 )
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	10	8/22/2024	NON-COMPETING CONTINUATION	$325,881
2024	2022	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	8	9/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $325,881

Issue Date FY: 2023 ( Subtotal = $336,881 )
2023	2023	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	9	9/21/2023	COMPETING CONTINUATION	$336,881
2023	2022	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	8	9/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $336,881

Issue Date FY: 2022 ( Subtotal = $322,472 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	8	6/28/2022	NON-COMPETING CONTINUATION	$322,472
														Subtotal = $322,472

Issue Date FY: 2021 ( Subtotal = $322,545 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	7	6/28/2021	NON-COMPETING CONTINUATION	$322,545
														Subtotal = $322,545

Issue Date FY: 2020 ( Subtotal = $320,588 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	6	6/25/2020	NON-COMPETING CONTINUATION	$320,588
2020	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	5/22/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $320,588

Issue Date FY: 2019 ( Subtotal = $326,559 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	5	8/30/2019	COMPETING CONTINUATION	$326,559
2019	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	4/29/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $326,559

Issue Date FY: 2018 ( Subtotal = $302,409 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	3/15/2018	NON-COMPETING CONTINUATION	$272,168
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	4	5/7/2018	NON-COMPETING CONTINUATION	$30,241
														Subtotal = $302,409

Issue Date FY: 2017 ( Subtotal = $298,499 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	3	4/14/2017	NON-COMPETING CONTINUATION	$268,649
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	3	7/24/2017	NON-COMPETING CONTINUATION	$29,850
														Subtotal = $298,499

Issue Date FY: 2016 ( Subtotal = $302,409 )
2016	2016	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	3/31/2016	NON-COMPETING CONTINUATION	$302,409
														Subtotal = $302,409

Issue Date FY: 2015 ( Subtotal = $298,499 )
2015	2015	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	7/31/2015	NEW	$298,499
														Subtotal = $298,499

Grand Total All Awards = $3,482,623

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Next-generation alchemical free energy methods and quantum/machine-learning models for drug discovery

Award Number: R01GM107485

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2015

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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