Research and Deployment of a quantum mechanical NMR tool for fragment based drug

Award Information
Agency: Department of Health and Human Services
Branch: N/A
Contract: 1R44GM099411-01
Agency Tracking Number: R44GM099411
Amount: $147,912.00
Phase: Phase I
Program: SBIR
Awards Year: 2011
Solicitation Year: 2011
Solicitation Topic Code: NIGMS
Solicitation Number: PA10-050
Small Business Information
DUNS: 172210572
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 (814) 235-6908
Business Contact
Phone: (814) 235-6908
Research Institution
DESCRIPTION (provided by applicant): Improving human health by enabling the development of drugs faster and cheaper is an important part of the NIH mission. This is partially achieved by introducing and constantly improving enabling technologies. One suchtechnology is structure based drug design. Determining the structure of a small molecule (drug candidate or lead compound) to a biological receptor (protein implicated in disease) is a necessary step in this methodology. The dominant experimental approachused to achieve this goal is X- ray crystallography, while nuclear magnetic resonance (NMR) plays a lesser role in spite of large investments both in academia and industry. NMR is hampered by the size of protein that can be studied and the need to go through a lengthy structure determination process. However, with the advent of fragment based drug design, NMR is playing a much larger role and it could play an even greater role if it was possible to reduce the time effort necessary to solve the structure ofa protein-ligand complex. Moreover, in cases where it is not possible to obtain a crystal NMR can play a significant role. Through the use of solid-state NMR studies membrane proteins or proteins with solubility problems can be studied or in cases where only homology models of a protein are available NMR could play a role through the validation of active site structure hypotheses generated in homology modeling studies. The aim of the proposed research is to extend and commercialize QuantumBio's successful linear-scaling semiempirical quantum mechanical NMR approach (NMRScore) to chemical shift perturbation (CSP) analysis through the addition of target-observed CSP and ab initio NMR methods. In Phase I of this proposal the limits of applicability will be explored. In the Phase II proposal extension of the methodology via reparameterization of 1H, 13C 17O and 15N NMR will be carried out and a new classical NMR predictor will be developed. Furthermore, the streamlining of the workflow will be researched and implemented. Finally, this proposal is aiming to fully productize and commercialize this breakthrough technology. It is anticipated that by making this application commercially available the use of NMR in structure-based design efforts will be enhanced and theNMR tool and service market size can be further expanded. Significantly, the tool-box of structure based drug design will gain an important new method which will enable drug development for targets inaccessible to today's mainstream drug discovery paradigm. Thus, in the near future important underserved diseases can be targeted more efficiently. PUBLIC HEALTH RELEVANCE: The successful completion of the Fast-Track SBIR grant will have a major impact on improving human health. It will improve the quality of protein structures, facilitate the understanding of biomolecular dynamics and will provide higher quality structural insights into protein/ligand (drug) interactions which will enhance our ability to rationally design novel therapeutics for human diseases.

* Information listed above is at the time of submission. *

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