Receptor flexibility

The first reason is that the ideal starting point for de novo design is a cocrystallized receptor-inhibitor complex. Subsequent design based on the receptor structure is known to be targeting an accessible conformation of the receptor. If high-scoring ligand conformations can be located (and here it is 

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Lin JH, Perryman AL, Schames JR, McCammon JA. 2002. Computational drug design accommodating receptor flexibility the relaxed complex scheme. J Am Chem Soc... 

Docking programs routinely incorporate compound flexibility. However, incorporating receptor flexibility in docking procedures is still a major hurdle (61). Of late, several attempts have been made for this purpose (cf (46, 62) for review). 

Lin, J. H., Perryman, A. L., Schames, J. R., and McCammon, J. A. (2003) The relaxed complex method accommodating receptor flexibility for drug design with an improved scoring scheme. Biopolymers 68,47-62. 

Armen RS, Chen J, Brooks CL (2009) An evaluation of explicit receptor flexibility in molecular docking using molecular dynamics... 

Amaro RE, Baron R, McCammon JA (2008) An improved relaxed complex scheme for receptor flexibility in computer-aided drug design. J Comput Aided Mol Des 22(9) 693-705... 

Morris GM, Huey R, Lindstrom Wet al (2009) AutoDock4 and AutoDockTools4 automated docking with selective receptor flexibility. J Comput Chem 30 2785-2791... 

All test set ligands were docked and scored as described in the methods section. For three compounds Auto Dock was not able to find any low energy conformation. A visual inspection of the binding site revealed that these compounds can only bind in a low energy conformation if several amino acids change their side-chain orientation. In the present version of AutoDock receptor flexibility cannot be considered. The remaining compounds were successfully docked by the Auto-... 

Receptor Flexibility in Computational Design Induced-Fit Versus Conformational Selection Enthalpy-Entropy Compensation (EEC) Allostery Conclusion... 

The consideration of a sufficient degree of protein flexibility needs to become part of standard docking approaches. This will require faster algorithms. In addition, with respect to scoring, an often overlooked aspect of this problem is that as soon as receptor flexibility is allowed, protein conformational energy changes need to be accounted for appropriately. 

M. Zacharias and H. Sklenar. Harmonic modes as variables to approximately account for receptor flexibility in ligand-receptor docking simulations Application to DNA minor groove ligand complex. Journal of Computational Chemistry, 20 287-300, 1999. 

Davis. l.W. and Baker, D. (2009) RosettaLigand docking with full ligand and receptor flexibility. Journal of Molecular Biology, 385, 381-392. 

Bottegoni, G., Kufareva, I.,Totrov, M., and Abagyan, R. (2009) Four-dimensional docking a fast and accurate account of discrete receptor flexibility in ligand docking. Journal of Medicinal Chemistry, 52, 397 06. 

Fleksy [102] is a docking protocol that incorporates the FlexE docking [53] engine already described in Section 8.2.1.2. Given an experimental input structure, the protocol generates multiple receptor conformations to introduce receptor flexibility. For rule-based identified or alternatively user-defined residues, it extracts some most... 

Cavasotto, C.N., Kovacs, J.A., and Abagyan, R.A. (2005) Representing receptor flexibility in ligand docking through relevant normal modes. Journal of the American Chemical Society, 127 (26), 9632-9640. 

Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S., and Olson, A.J. (2009) AutoDock4 and AutoDockTools4 automated docking with selective receptor flexibility. Journal of Computational Chemistry, 30 (16), 2785-2791. 

The impact of receptor flexibility on docking is usually assessed by cross-docking experiments, whereby a series of ligands is docked to all their corresponding... 

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