Saturday, November 23, 2024 11/23/2024

Pharmacophore-Directed Retrosynthesis Applied to Bioactive Natural Products Informing Mechanism of Action Studies

Award Number: R35GM134910
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract While ‘diversity-oriented,’ ‘biology-oriented,’ and ‘analogue-oriented’ syntheses have contributed to Wender’s call for ‘function-oriented synthesis,’ the simultaneous alignment of total synthesis efforts with structure activity relationship (SAR) studies has not been fully realized. This is particularly true with natural products where little to no SAR information exists. Bringing hypotheses regarding a targeted natural product's pharmacophore into the retrosynthetic planning stages of a total synthesis effort would dramatically accelerate the identification of simplified, bioactive derivatives as lead compounds for therapeutic intervention. Our chemical and biological studies of natural products possessing a broad range of cellular effects will be guided by the following inquiry: Can total synthesis efforts, in particular with limited SAR and unknown cellular targets, be more closely aligned to biological studies by targeting designed derivatives possessing a hypothesized pharmacophore during the retrosynthetic planning stages to enable SAR studies to be conducted en route to the natural product? Our study will develop a type of innovative retrosynthetic analysis that more closely aligns total synthesis efforts with concurrent biological studies. We term this strategy ‘pharmacophore- directed retrosynthesis’ (PDR) to emphasize the importance of considering hypothesized pharmacophores at the retrosynthetic planning stage of a total synthesis effort. This approach will importantly lead to the identification of simplified versions of the natural product with similar potency or potentially new functions in route to the natural product. While this approach increases the challenges of natural product total synthesis beyond important, contemporary goals, including atom-economy, step and redox efficiency, and protecting group avoidance, significantly it will greatly accelerate harvesting of the vast information content of natural products for basic cell biology and medicine. This strategy begins with a hypothesized pharmacophore for a bioactive natural product which informs and directs the retrosynthetic strategy. Stepwise, methodical introduction of complexity to the hypothesized pharmacophore enables concurrent SAR data collection which in turn informs cellular probe synthesis. A fruitful group of ongoing collaborators, including molecular, cell, and cancer biologists and chemical biologists will utilize our natural product-based probes to contribute to fundamental advances in cell biology. Overall, our proposed synthetic studies, combined with collaborative biological studies, will both open new avenues for novel therapeutics, and contribute to a greater understanding of basic cellular mechanisms involved in human disease including bacterial infection, inflammation, cardiovascular, Alzheimer’s disease, and cancer. The proposed research will demonstrate the importance of closely engaging total synthesis efforts with biological studies of natural products at the retrosynthetic planning stages. We will demonstrate the utility of PDR for reverse chemical genetic explorations of natural products towards identification of new drug leads and novel cellular targets critical to uncovering new avenues to impact human health.


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 = $0 )
2025	2024	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	000	5	11/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $360,100 )
2024	2024	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	001	5	5/20/2024	NON-COMPETING CONTINUATION	$36,010
2024	2024	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	000	5	1/1/2024	NON-COMPETING CONTINUATION	$324,090
														Subtotal = $360,100

Issue Date FY: 2023 ( Subtotal = $360,100 )
2023	2023	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	000	4	2/17/2023	NON-COMPETING CONTINUATION	$360,100
														Subtotal = $360,100

Issue Date FY: 2022 ( Subtotal = $390,100 )
2022	2022	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	001	3	6/24/2022	NON-COMPETING CONTINUATION	$39,010
2022	2022	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	000	3	1/4/2022	NON-COMPETING CONTINUATION	$351,090
														Subtotal = $390,100

Issue Date FY: 2021 ( Subtotal = $499,513 )
2021	2021	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	002	2	7/12/2021	SUPPLEMENT FOR EXPANSION	$99,788
2021	2021	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	001	2	2/12/2021	NON-COMPETING CONTINUATION	$39,973
2021	2021	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	000	2	12/8/2020	NON-COMPETING CONTINUATION	$359,752
														Subtotal = $499,513

Issue Date FY: 2020 ( Subtotal = $273,570 )
2020	2020	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	000	1	1/1/2020	NEW	$273,570
														Subtotal = $273,570

Grand Total All Awards = $1,883,383

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Pharmacophore-Directed Retrosynthesis Applied to Bioactive Natural Products Informing Mechanism of Action Studies

Award Number: R35GM134910

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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