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Acpharis awarded NIH STTR Grant: “High-throughput portable software for fragment-based drug design”

Acpharis announced today that it has been awarded an NIH STTR grant application entitled “High-throughput portable software for fragment-based drug design”. The NIH STTR program is intended to stimulate a partnership of ideas and technologies between innovative small business concerns (SBCs) and non-profit research institutions through Federally-funded research or research and development (R/R&D). By providing awards to SBCs for cooperative R/R&D efforts with non-profit research institutions, the STTR program assists the small business and research communities by commercializing innovative technologies.

The general goal of this proposal is to develop portable fragment-based drug design (FBDD) software product called 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. 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 appropriate targets 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 published novel, efficient, and highly accurate methods for computational solvent mapping. 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 computational solvent mapping 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. Atlas will include a computational solvent 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 in order 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.