High-throughput portable software for fragment-based drug design

Award Information
Agency: Department of Health and Human Services
Branch: N/A
Contract: 1R41GM097907-01
Agency Tracking Number: R41GM097907
Amount: $98,055.00
Phase: Phase I
Program: STTR
Awards Year: 2011
Solicitation Year: 2011
Solicitation Topic Code: NIGMS
Solicitation Number: PA10-051
Small Business Information
DUNS: 830023755
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 (617) 353-4757
Business Contact
Phone: (617) 353-4795
Email: rbrenke@acpharis.com
Research Institution
BOSTON, MA, 02215-
 () -
 Nonprofit college or university
DESCRIPTION (provided by applicant): Fragment-based drug design (FBDD) is a combinatorial approach in which individual fragments binding to regions of the target site are selected from a fragment library, and then combined to form potential lead compounds.Interest in this approach has significantly increased during the last few years, with many companies using FBDD methods based on X-ray crystallography or NMR. Although computational methods can potentially reduce the price of FBDD by selecting appropriatetargets as well as fragments with increased probability of success, all methods that that explore the binding of fragment-sized ligands to proteins are at least 15 years old, and hence do not account for the recent progress. The Vajda lab at Boston University has been developing methods for the mapping of proteins and has recently released the efficient and highly accurate mapping program FTMAP. The method moves molecular probes - small organic molecules containing various functional groups - around the protein to find binding hot spots with preference for specific functional groups. The goals of this proposal are (1) developing FTMAP into an effective and portable FBDD software product called Atlas, and (2) in a second stage of development, adding computational steps to Atlas for the design of inhibitors that target protein-protein interactions. The programs from the Vajda group to be included in Atlas are the FTMAP mapping program, a program developed for generating alternative side chain conformers, a program for iterative mapping to identify functional groups that preferentially bind to a target site, and the protein-protein docking program PIPER. Acpharis will develop five additional programs that (1) perform virtual screening using generalized pharmacophores based on the mapping results; (2) effectively communicate the results to medicinal chemists for the design of larger compounds from the fragment hits identified; (4) implement an innovative fragment based algorithm for ranking homologous compounds inorder to optimize R-groups for a given scaffold; (4) prepare protein structures for mapping, and (5) construct extended and target-specific probe libraries, including the parameterization of the molecules. All elements will be combined into a powerful FBDD software package called Atlas which will be implemented both on multi- core processors and as a cloud-computing based virtual machine built on Amazon's Elastic Compute Cloud. The use of Atlas will reduce the number of X-ray crystallography or NMR based screening experiments required for FBDD, and hence will substantially reduce the costs associated with this approach, an important consideration for small companies and academic labs. PUBLIC HEALTH RELEVANCE: Fragment-based drug design (FBDD) is a combinatorial approach in which individual fragments binding to regions of a target site are selected from a fragment library, and then combined to form potential lead compounds. The general goal of this proposal is to develop portable FBDD software productcalled ATLAS that, at least in the early stages of the design, can provide a viable alternative to the expensive fragment screening by Nuclear Magnetic Resonance or X-ray crystallography.

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

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