Conformations bioactive

The conformation of a ligand which binds to an enzyme and behaves either as a substrate or an inhibitor. 

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Miller and Rich assumed that cyclosporin Aand itsMeBmt analogs share a common bioactive conformation. Their molecular mechanics calculations found such a conformation. The Boltzmann population of the proposed bioactive conformation correlates with the immunosuppressive activities of the compounds. 

This effect is particularly well documented for y - and -amino acid residues [217, 218] which in several natural products (bleomycin A2 [219], calyculins [220]) have been shown to play a substantial role in the pre-organization of the whole molecule into its bioactive conformation. For example, changes in the substitution pattern of the y-amino acid linker in bleomycin A2 result in reduced DNA cleavage efficiency [219]. In the case of y-peptides, changing the relative configuration like or unlike of y " -amino acids has been used as a strategy to generate different local conformations (Fig. 2.34) suitable either for the construction of helices [201] or turns ]202-204]. 

This chapter summarizes the computational methodologies used for conformational analysis. Specifically, Section 8.1 gives a theoretical outUne of the problem and presents details of various implementations of computer codes to perform conformational analysis. Section 8.2 describes calculations illustrative of the current accuracy in generating the conformation of a ligand when bound to proteins (the bioactive conformer) by comparisons to crystaUographically observed data. Finally, Section 8.3 concludes by presenting some practical... 

Fig. 8.4 The global energy minima of compound 17 in gas phase and in solution are virtually identical. The energy difference between lowest energy conformation (a) and the bioactive conformation (b) in gas phase is 13.4kcal molAlthough a folded...

Reproducing Bioactive Conformations Using Different Duplicate Removal Values... 

Figure 8.5 shows for different values of the duphcate removal parameter - the number of ligands for which the OMEGA conformation reproduces the bioactive conformation. It can be seen that the value of the duplicate removal parameter has a significant effect on the ability to reproduce the experimental bioactive conformation. Low values of the -rms parameter reproduce greater than 65% of the bioactive conformations, whereas for high values the number converges to approximately 30%. 

Confort s [14] refinement procedure. Previous studies show that these functions do not increase the likelihood of retrieving the bioactive conformation on the contrary, they have a negative impact [35],... 

Certain computational methodologies such as some approaches to quantitative structure-activity relationship (QSAR) studies use 3D ligand structures [37, 38]. These methods generally assume that a bioactive conformation has been estab-Hshed for a set of molecules and that these conformers can be ahgned in a maimer that reflects the relative orientation they would adopt in a binding site. It is thus... 

J. Assessing the performance of OMEGA with respect to retrieving bioactive conformations. J. Mol. Graph. Model. 2003, 21, 449-462. 

It is important to note that most molecules are not rigid but may prefer a distrinct structure and the conformation of a molecule strongly depends on its specific environment. Hence, the crystal structure of a drug does not have to correspond to the receptor bound conformation. Also, a conformation in solution depends on the nature of the solvent and measuring conditions, and may change when the molecule is bound to the receptor [4]. In addition, different receptors or receptor subtypes can bind the same drug in different conformations. It is a general assumption and observation, but by far not a strict condition, that the conformation in aqueous solution is similar to the bound conformation and is a better representation of the bioactive conformation than an X-ray structure of the isolated molecule in the crystalline state. 

Weide T, Modlinger A, Kessler H (2007) Spatial Screening for the Identification of the Bioactive Conformation of Integrin Ligands. 272 1-50 Weiss EA, Wasielewski MR, Ratner MA (2005) Molecules as Wires Molecule-Assisted Movement of Charge and Energy. 257 103-133... 

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