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From atoms to mechanisms - Artificial Intelligence augmented molecular simulations for mechanistic ligand design

Award Number: R35GM142719
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: 09/18/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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From atoms to mechanisms - Artificial Intelligence augmented molecular simulations for mechanistic ligand design - While there have been numerous advances in computational methods aiding in rational drug design, most approaches so far take a static view of the drug target, ignoring the complexities associated with the dynamics and thermodynamics of conformational transitions. There is thus a pressing need for new computational methods that are accurate, tractable and automatable for large scale drug discovery and chemical biology studies that account for the changing nature of a generic drug target. Built on strong theoretical and computational preliminary results, this program seeks to understand and guide design of new inhibitors of tyrosine kinases and model riboswitches in a mechanistically guided paradigm. Our research program is driven by the central hypotheses that (a) mechanistically aware ligand design strategies can outperform traditional strategies guided only by structure, and (b) artificial intelligence (AI)- integrated molecular dynamics (MD) simulation methods can help learn mechanisms in a high-throughput fashion. Our program can be split into two overarching yet complementary thematic areas. In the first area, we will develop sampling algorithms at the interface of statistical mechanics, MD simulations and AI to probe mechanisms for rare event processes, such as drug unbinding and conformational change. Specifically we will build on our preliminary work in using ideas from neural information processing and natural language processing, and adapt them for advanced sampling methods that learn reaction coordinate, thermodynamics and kinetics on-the-fly as the simulation progresses. In addition, we will also be interacting closely with other leading computational groups to integrate our sampling methods with theirs and to facilitate efficient, accurate sampling for polarizable force-field development. In the second area, we will use our algorithms to guide mechanistically driven design of inhibitors of Src, Abl kinases and PreQ1 riboswitches. We will take a mechanistically driven perspective wherein we will map out the different conformations of a given target and understand how an existing ligand interacts with these, and then propose ligand modifications based upon this understanding. We will use our AI-augmented MD methods to understand the dissociation mechanisms of ligands in one uninterrupted “atoms to mechanism” workflow with minimal human intervention. All our predictions will be validated in different ways by our experimental collaborators at Stony Brook University and the National Cancer Institute


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 = $393,209 )
2025	2025	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	001	5	8/26/2025	SUPPLEMENT FOR EXPANSION	$19,454
2025	2025	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	5	8/12/2025	NON-COMPETING CONTINUATION	$373,755
														Subtotal = $393,209

Issue Date FY: 2024 ( Subtotal = $509,935 )
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	3	2/23/2024	SUPPLEMENT FOR EXPANSION	$58,363
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	002	4	8/16/2024	SUPPLEMENT FOR EXPANSION	$77,817
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	001	4	8/15/2024	NON-COMPETING CONTINUATION	$373,755
														Subtotal = $509,935

Issue Date FY: 2023 ( Subtotal = $373,755 )
2023	2023	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	3	8/29/2023	NON-COMPETING CONTINUATION	$373,755
														Subtotal = $373,755

Issue Date FY: 2022 ( Subtotal = $373,755 )
2022	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	2	8/12/2022	NON-COMPETING CONTINUATION	$373,755
														Subtotal = $373,755

Issue Date FY: 2021 ( Subtotal = $373,755 )
2021	2021	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	1	9/17/2021	NEW	$373,755
														Subtotal = $373,755

Grand Total All Awards = $2,024,409

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From atoms to mechanisms - Artificial Intelligence augmented molecular simulations for mechanistic ligand design

Award Number: R35GM142719

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: 09/18/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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