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Combining structure-based network biology and heterogeneous computing for rational drug repositioning and polypharmacology

Award Number: R35GM119524
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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1. Project Summary Drugs are typically developed to modulate the function of specific proteins, which are directly associated with particular disease states. Nonetheless, recent studies suggest that protein-drug interactions are promiscuous and the majority of pharmaceuticals exhibit activity against multiple, often unrelated proteins. The lack of selectivity often leads to undesired drug side effects; yet, these polypharmacological attributes can be used to develop drugs that act on multiple targets of a unique disease pathway, as well as to identify new targets for existing drugs, known as drug repositioning. Although predicting interactomes is becoming increasingly important in drug discovery, a large number of interacting molecules and highly complicated interaction patterns present significant challenges. Clearly, novel computational approaches are desperately needed to rigorously explore drug cross-reactivity. The overall goal of the proposed research is, therefore, to combine a broad scope and promises of computational systems biology, atomic-level modeling of medically relevant biomolecules and interactions among them, and heterogeneous computing using massively parallel accelerators to study drug-oriented interactomes. This innovative project comprises several components. First is to design a fully automated platform for structure-based ligand virtual screening featuring an information theory-based compound selection. By using the Maximum Entropy Method, we will be able to enhance the specificity of scoring functions for ligand ranking. Second, we plan to improve the across-proteome identification of chemically similar drug binding pockets by combining local binding site alignment with molecular docking. The advantage of this new strategy is the capability to explore a much larger space of putative cross-interactions between proteins and small organic compounds. Third, we are going to use new modeling techniques described above to reconstruct and investigate protein-drug interaction networks in the human proteome. By developing novel multi-target antibiotics, we will demonstrate that the proposed network analysis greatly expands the current opportunity space for polypharmacology and rational drug repositioning. Fourth, the scale of the task at hand as well as the level of details put an unprecedented demand for computing resources. Consequently, there is an urgent need to take advantage of modern computer architectures currently available as well as exascale supercomputers that are expected to come into production in the near future. On that account, we plan to develop high-performance codes to fully utilize heterogeneous machines equipped with massively parallel hardware accelerators, NVIDIA GPU and Intel Xeon Phi. Close collaborations with experimental and computer science groups will be part of the proposed research to make advances in this highly specialized field. The expected overall impact of this innovative proposal is that it will 1) fundamentally advance our understanding of protein-drug interaction networks and 2) use this knowledge along with cutting-edge computing technology to support the development of novel therapies.


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: 2023 ( Subtotal = -$496 )
2023	2020	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Biomedical Research and Research Training	000	5	3/29/2023	NON-COMPETING CONTINUATION	-$496
														Subtotal = -$496

Issue Date FY: 2020 ( Subtotal = $192,411 )
2020	2020	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Biomedical Research and Research Training	000	5	7/30/2020	NON-COMPETING CONTINUATION	$192,411
														Subtotal = $192,411

Issue Date FY: 2019 ( Subtotal = $192,411 )
2019	2019	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Biomedical Research and Research Training	000	4	7/26/2019	NON-COMPETING CONTINUATION	$192,411
														Subtotal = $192,411

Issue Date FY: 2018 ( Subtotal = $192,411 )
2018	2018	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Biomedical Research and Research Training	000	3	6/22/2018	NON-COMPETING CONTINUATION	$192,411
														Subtotal = $192,411

Issue Date FY: 2017 ( Subtotal = $192,411 )
2017	2017	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Biomedical Research and Research Training	000	2	6/14/2017	NON-COMPETING CONTINUATION	$192,411
														Subtotal = $192,411

Issue Date FY: 2016 ( Subtotal = $192,411 )
2016	2016	LOUISIANA STATE UNIV AND A&M COLLEGE	THOMAS BOYD HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Biomedical Research and Research Training	000	1	7/14/2016	NEW	$192,411
														Subtotal = $192,411

Grand Total All Awards = $961,559

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Combining structure-based network biology and heterogeneous computing for rational drug repositioning and polypharmacology

Award Number: R35GM119524

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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