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Synthesizability-constrained expansion and multi-objective evolution of antitubercular compounds

Award Number: R21AI169342
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY New approaches are urgently needed to advance new chemical entities as antitubercular agents of clinical relevance. A key hurdle is the multiple criteria process that constitutes hit-to-lead optimization of small molecules with demonstrated in vitro potency versus drug-sensitive and drug-resistant strains of the causative bacterium Mycobacterium tuberculosis (Mtb). This project will address the design, construction, and validation of novel machine learning approaches to predict two of these critical molecular properties: in vitro Mtb growth inhibition and mouse pharmacokinetic exposure in the plasma. The resulting models, validated through external test statistics, will be complemented by computational approaches, relying on expert-encoded reaction templates and/or learned reaction prediction models, to predict optimal synthetic routes to two promising antitubercular small molecules: JSF-3005 and CD117. These data will inform the enumeration of synthesizable analogs for hit expansion to be followed by the selection of candidate analogs scored with a multi-objective Pareto optimization criterion combining multiple surrogate QSAR models with or without docking scores. Optimality scores will guide a genetic algorithm for synthesizability-constrained molecular optimization as a replacement for exhaustive forward enumeration. The top-scoring candidate lead compounds in each series will be then assayed for critical molecular properties to validate this novel approach and supply novel antitubercular agents for further study outside the scope of this proposal.


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: 2024 ( Subtotal = $0 )
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	001	2	12/14/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$77,476
2024	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	1	12/14/2023	NEW	-$77,476
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $242,025 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	001	2	2/22/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$242,025
2023	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	1	2/22/2023	NEW	$0
														Subtotal = $242,025

Issue Date FY: 2022 ( Subtotal = $197,349 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	1	3/18/2022	NEW	$197,349
														Subtotal = $197,349

Grand Total All Awards = $439,374

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Synthesizability-constrained expansion and multi-objective evolution of antitubercular compounds

Award Number: R21AI169342

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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