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FLOG: A system to select ‘quasi-flexible’ ligands complementary to a receptor of known three-dimensional structure (1994)

Miller, Michael D. ; Kearsley, Simon K. ; Underwood, Dennis J. ; [et al.]

Springer

Journal of computer aided molecular design 8 (1994), S. 153-174

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ISSN: 1573-4951

Keywords: DOCK ; Dihydrofolate reductase ; Merck Index ; 3D databases

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Summary We present a system, FLOG (Flexible Ligands Oriented on Grid), that searches a database of 3D coordinates to find molecules complementary to a macromolecular receptor of known 3D structure. The philosophy of FLOG is similar to that reported for DOCK [Shoichet, B.K. et al., J. Comput. Chem., 13 (1992) 380]. In common with that system, we use a match center representation of the volume of the binding cavity and we use a clique-finding algorithm to generate trial orientations of each candidate ligand in the binding site. Also we use a grid representation of the receptor to assess the fit of each orientation. We have introduced a number of novel features within this paradigm. First, we address ligand flexibility by including up to 25 explicit conformations of each structure in our databases. Nonhydrogen atoms in each database entry are assigned one of seven atom types (anion, cation, donor, acceptor, polar, hydrophobic and other) based on their local bonded chemical environments. Second, we have devised a new grid-based scoring function compatible with this ‘heavy atom’ representation of the ligands. This includes several potentials (electrostatic, hydrogen bonding, hydrophobic and van der Waals) calculated from the location of the receptor atoms. Third, we have improved the fitting stage of the search. Initial dockings are generated with a more efficient clique-finding algorithm. This new algorithm includes the concept of ‘essential points’, match centers that must be paired with a ligand atom. Also, we introduce the use of a rapid simplex-based rigid-body optimizer to refine the orientations. We demonstrate, using dihydrofolate reductase as a sample receptor, that the FLOG system can select known inhibitors from a large database of drug-like compounds.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00119865

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A systematic search for protein signature sequences (1992)

Sheridan, Robert P. ; Venkataraghavan, R.

New York, NY : Wiley-Blackwell

Proteins: Structure, Function, and Genetics 14 (1992), S. 16-28

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ISSN: 0887-3585

Keywords: BLAST3 ; protein sequence ; sequence motif ; protein sequence database ; Chemistry ; Biochemistry and Biotechnology

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Medicine

Notes: Signature sequences are contiguous patterns of amino acis 10-50 resiues long that are associated with a particular structure or function in proteins. These may be of three types (by our nomenclature): superfamily signatures, remnant homologies, and motifs. We have performed a systematic search through a database of protein sequences to automatically and preferentially find remnant homologies and motifs. This was accomplished in three steps: 1We generated a nonredundant sequence database.2We used BLAST3 (Altschul and Lipman, Proc. Natl. Acad. Sci. U.S.A. 87:5509--5513, 1990) to generate local pairwise and triplet sequence alignments for every protein in the database vs. every other.3We selected “interesting” alignments and grouped them into clusters. We find that most of the clusters contain segments from proteins which share a common structure or function. Many of them correspond to signatures previously noted in the literature. We discuss three previously recognized motifs in detail (FAD/NAD-binding, ATP/GTP-binding, and cytochrome b5-like domains) to demonstrate how the alignments generated by our procedure are consistent with previous work and make structural and functional sense. We also discuss two signatures (for N-acetyltransferases and glycerol-phosphate binding) which to our knowledge have not been previously recognized. © 1992 Wiley-Liss, Inc.

Additional Material: 6 Ill.