Conformationally flexible docking

GeUiaar D K, G M Verkhivker, P A Rejto, C J Sherman, D B Fogel, L J Fogel and S T Freer 1995 Molecular Recognition of the Inhibitor AG-1343 by HFV-l Protease Conformationally FlexibL Docking by Evolutionary Programming. Chemistry and Biology 2 317-324. 

Rejto, P.A., Sherman, C.J., and Fogel, D.B. Molecular recognition of the inhibitor AG-1343 by HlV-1 protease conformationally flexible docking by evolutionary programming. Chem. Biol. 1995, 2, 317-324. 

Gehlhaar DK, Verkhivker GM, Rejto PA, Sherman CJ, Fogel DB, Fogel LJ, Freer ST. Molecular recognition of the inhibitor Ag-1343 by Hiv-1 protease—conformationally flexible docking by evolutionary programming. Chem Biol 1995 2 317-324. 

J. M. Blaney, D. W ininger, and J. S. Dixon, Molecular Graphics Society Meeting, Universitiy of York, UK, March 28, 1993. Conformationally Flexible Docking and Evolution of Molecules to Fit a Binding Site of Known Structure. 

A computational procedure for fitting molecules into an active site of an enzyme to determine which ones will bind most tightly. Docking can be done on a single static conformation of each molecule, but works better when multiple static conformations are used, or when the ligand is allowed to alter its conformation (flexible docking). 

An overview of docking programs is given in Tabic 10.4-3. Depending on the way the conformational flexibility of the ligand is treated, docking can be either rigid or flexible. 

A successful application of GA to conformation sampling is, for example, as a part of flexible docking [12-14], It should be noted, however, that none of the three sampling methods discussed above, MD, MC, and GA, was shown to outperform the other two in any general way. In fact, a comparison of the three methods in the context of flexible docking showed similar efficiency for all three [12], although specific advantages are likely to exist for particular apphcations. 

Bcl-2 is one of the many factors that control apoptosis, and overexpression of Bcl-2 has been observed in many different cancers. A homology model of Bcl-2 was derived from the NMR 3D structure of the Bcl-XL complex with a Bak BH3 peptide. This model served to search the NCI 3D database of 206,876 organic compounds for potential Bcl-2 inhibitors, which bind to the Bak BH3 binding site of Bcl-2. Full conformational flexibility of the ligands was taken into account in the program DOCK. Thirty-five potential inhibitors were tested, and seven of them had IC50 values from 1.6 to W.OpM. One of... 

L, Guida W. C. Low-mode conformational search elucidated Application to C39H80 and flexible docking of 9-deazaguanine inhibitors into PNP. /. Comput. Chem. 1999, 20,1671-1684. 

Virtual screening applications based on superposition or docking usually contain difficult-to-solve optimization problems with a mixed combinatorial and numerical flavor. The combinatorial aspect results from discrete models of conformational flexibility and molecular interactions. The numerical aspect results from describing the relative orientation of two objects, either two superimposed molecules or a ligand with respect to a protein in docking calculations. Problems of this kind are in most cases hard to solve optimally with reasonable compute resources. Sometimes, the combinatorial and the numerical part of such a problem can be separated and independently solved. For example, several virtual screening tools enumerate the conformational space of a molecule in order to address a major combinatorial part of the problem independently (see for example [199]). Alternatively, heuristic search techniques are used to tackle the problem as a whole. Some of them will be covered in this section. 

Sandak, B., Nussinov, R., and Wolfson, H.J. A method for biomolecular stmctural recognition and docking allowing conformational flexibility. 

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