Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Developing high-throughput free energy methods for small molecule, peptide, and protein design

Award Number: R35GM162544
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: 08/22/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

Group Awards By:

View Award Description

Developing high-throughput free energy methods for small molecule, peptide, and protein design - Project Summary/Abstract The discovery and design of therapeutic drugs, including small molecules, peptides, and engineered proteins, are essential for advancing the field of medicine and improving the quality of life. Computational approaches that leverage fundamental physical principles, as well as available structural and functional data of the drug target, can enable more efficient usage of experimental resources, thus reducing the cost and time span of the overall process. Computational tools, such as docking, pharmacophore mapping, and machine learning, can be highly successful in exploring large chemical and protein sequence spaces to identify a small set of lead molecules that show promising activities. Moving beyond the initial discovery stage, rigorous physics-based free energy approaches are often required to more accurately assess and optimize lead molecules. However, a major bottleneck associated with popular free energy methods is the computational cost and thus limited throughput, especially when substantial conformational flexibility exists for the receptor and/or the ligand. To address this bottleneck, we propose to integrate enhanced sampling methods with multisite l dynamics (MSlD) to achieve an effective computational framework, hereafter referred to as MSlD++, for rigorous high-throughput free energy predictions in drug discovery and design. MSlD enables the modeling of multiple substituents at multiple sites of a common ligand core and can yield free energies for thousands of molecules in a single simulation. It is thus particularly powerful for solving the combinatorial complexity in the exploration of chemical and protein sequence space frequently involved in lead optimization. Furthermore, this unique feature of MSlD allows one to run much longer simulations and/or incorporate more sophisticated simulation techniques to adequately sample protein and ligand dynamics for accurate high-throughput free energy calculations, even for challenging cases involving various levels of structural flexibility. The proposed MSlD++ development will be coupled with three important classes of applications with an increasing level of complexity and demand for conformational sampling: (1) Efficient sampling of protein local structural changes in small molecule drug discovery; 2) Design of potent and selective therapeutic peptides; (3) Understanding and engineering transcription factors for DNA recognition. Successful development of MSlD++ algorithms will push the limit of accuracy and throughput for free energy- based approaches in the rational design of small-molecule drugs, therapeutic peptides, and functional proteins. Throughout the project, we will engage in close experimental collaborations to critically evaluate the effectiveness of MSlD++, thus allowing us to deliver robust tools to the broad scientific community.


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: 2026 ( Subtotal = $370,940 )
2026	2026	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Biomedical Research and Research Training	000	1	8/21/2026	NEW	$370,940
														Subtotal = $370,940

Grand Total All Awards = $370,940

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Developing high-throughput free energy methods for small molecule, peptide, and protein design

Award Number: R35GM162544

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: 08/22/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer