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Covalent protein-ligand binding affinities with VM2

Award Number: R44GM137634
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: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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Covalent protein-ligand binding affinities with VM2 - Project Summary Small molecule structure based drug design efforts in the pharmaceutical industry have, until recently, focused on the reversible non-covalent binding of ligands with target proteins. An alternative mechanism is the covalent binding of the ligand to the target protein, with around 30% of currently marketed drugs falling into this category. However, for most of these drugs, the covalent binding mechanism was serendipitous, not a design strategy, with their mechanism of action discovered long after their clinical utility had been established. Penicillin and aspirin are prominent examples of this. Despite the inherent advantages provided by the covalent binding mechanism, such as increased potency and increased residence times, it was purposefully avoided as a design strategy due to concerns that irreversible off- target interactions would lead to increased risk of toxicity and immunological response. However, the emergence of strategies to mitigate these risks, thereby allowing development of so-called targeted covalent inhibitors (TCIs), has prompted the establishment of numerous pharmaceutical industry covalent inhibitor drug discovery programs. The basic design strategy employed by TCI discovery programs aims at achieving a two-step process that first starts with reversible non- covalent binding with the target protein, followed by covalent bond formation between an electrophile on the ligand (often called a warhead) and a nucleophilic center in the protein. This multifaceted nature of the TCI mechanism for selectivity and potency is challenging for structure based discovery efforts. Furthermore, the current absence of computational tools that can provide accurate quantitative insight means that optimization of TCIs must be done exclusively by expensive and repeated rounds of synthesis, assay, and X-ray crystallography. The aim of this fast-track SBIR proposal, then, is to develop a novel molecular modeling software tool that can provide thermodynamic binding as well as reaction reversibility information for purposes of ranking prospective covalent inhibitor molecules. This tool will calculate free energies of covalent binding of candidate molecules to targeted protein residues, as well as free energies of binding for the pre- reactive non-covalent binding step. It will also provide a calculated free energy-based estimate of reaction reversibility. This software will be based on mining minima free energy calculation methodology and will be developed as an extension of VeraChem’s VM2 free energy software platform.


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	2022	VERACHEM LLC	12850 MIDDLEBROOK RD STE 205	GERMANTOWN	MD	20874	MONTGOMERY	USA	Biomedical Research and Research Training	000	3	5/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $785,946 )
2022	2022	VERACHEM LLC	12850 MIDDLEBROOK RD STE 205	GERMANTOWN	MD	20874	MONTGOMERY	USA	Biomedical Research and Research Training	000	3	12/1/2021	NON-COMPETING CONTINUATION	$785,946
														Subtotal = $785,946

Issue Date FY: 2021 ( Subtotal = $835,166 )
2021	2021	VERACHEM LLC	12850 MIDDLEBROOK RD STE 205	GERMANTOWN	MD	20874	MONTGOMERY	USA	Biomedical Research and Research Training	000	2	12/3/2020	EXTENSION WITH OR WITHOUT FUNDS	$835,166
2021	2020	VERACHEM LLC	12850 MIDDLEBROOK RD STE 205	GERMANTOWN	MD	20874	MONTGOMERY	USA	Biomedical Research and Research Training	001	1	5/16/2021	NEW	$0
														Subtotal = $835,166

Issue Date FY: 2020 ( Subtotal = $251,379 )
2020	2020	VERACHEM LLC	12850 MIDDLEBROOK RD STE 205	GERMANTOWN	MD	20874	MONTGOMERY	USA	Biomedical Research and Research Training	000	1	4/2/2020	NEW	$251,379
														Subtotal = $251,379

Grand Total All Awards = $1,872,491

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Covalent protein-ligand binding affinities with VM2

Award Number: R44GM137634

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: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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