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fFlash: 3D Molecular Similarity Search
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3D molecular similarity search is one of many tools used in computational drug design, and is particularly
relevant when the structures of ligands that bind to a receptor are known, but the structure of the
receptor is not. The goal is then to find all molecules within a database that match a "query" molecule
based on chemical similarity. Our approach, embodied in the 3D fFLASH search system, takes the torsional
flexibility of the database molecules fully into account, and can deal with an arbitrary number of
conformation-dependent molecular features. The method uses a fragmentation-reassembly approach in
conjunction with a special graph-based pattern-matching algorithm. Pairs of adjacent molecular fragments
are aligned to a rigid query molecule and subsequently reassembled to complete database molecules. fFLASH
is able to rapidly produce accurate alignments of medium-sized drug-like molecules. Experiments with a
test database containing a diverse set of 1,780 drug-like molecules (including some 5 billion possible
conformers) have shown that average query processing times of about one-tenth of a second per molecule can
be achieved on a PC depending on the size of the query molecule.
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2D structures of the molecules dihydrofolate and methotrexate.
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Result for a 3D feature-based alignment of methotrexate (flexible, bold lines)
and dihydrofolate (rigid, thin lines) (matching features are shown as pairs of colored spheres).
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Score plot illustrating the result of an fFLASH database query using dihydrofolate
as the query molecule. The database contains 1,780 compounds including 1,728 molecules from the NCI diversity set (blue circles),
50 known dihydrofolate reductase (DHFR) inhibitors (green triangles), methotrexate (red square) and the natural ligand dihydrofolate
itself (purple diamond). fFLASH finds dihydrofolate, methotrexate and about 50 percent of the DHFR actives as the highest scoring molecules
clearly separated from the cloud that represents the diversity set. The database query was completed within 3 minutes on a PC while
taking the torsional flexibility of the molecules fully into account.
The fFLASH project is currently being pursued in collaboration with the Molecular Design Group at Trinity College, Dublin, Ireland.
References
Andreas Kraemer, Hans W. Horn and Julia E. Rice, Fast 3D Molecular Superposition and Similarity Search in Databases of Flexible Molecules, JCAMD 2003, 17(1): p. 13-38.
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