Pharmacophore molecular flexibility

The peculiar features of the three arAR supermolecules were translated into pharmacophore hypotheses by means of Catalyst software (Figure 8.2, unpublished results). Catalyst treats molecular structures as templates placing chemical functions in 3D space to interact with the receptor. Molecular flexibility is taken into account by considering each compound as a collection of conformers representing different areas of the molecules conformational space within a given energy range. 

HY) as possible features. Two additional constraints were set (i) because of the molecular flexibility and functional complexity of the training set, only pharmacophores containing five features should be considered and (ii) the program was forced to include a positive ionizable feature in the composition of hypotheses, on the basis of the literature reporting a basic atom (usually a nitrogen) as a critical structural determinant for arAR antagonistic activity. 

Unique is the number of unique 3-point pharmacophores displayed by the whole library, Conscore is a term that can force a design to fill specific 3-point pharmacophores and avoid others i.e. to complement an existing compound collection). Partscore is used to force a distribution of shape related descriptors heavy atoms (ha), largest triangle perimeter for a pharmacophore in the library (pp) and largest triangle are for a pharmacophore in the library (pa). S is the total number of molecules that pass certain filters, such as a limit of molecular flexibility. Totpharm is the total of pharmacophores displayed by the entire library and Flex is the normalised number of conformations accessed by the library of n molecules. The terms a, b, Y and Z are user defined weights. 

In this article, we will explore the means by which molecules bind to enzymes and so behave as competitive inhibitors. We will then review the importance of pharmacophores in this process and the meth< used to identify, characterize, and search for pharmacophores. Finally, the role played by molecular flexibility, the thermodynamics of binding, and the impact of the pharmacophore concept upon drug design will be examined. 

Jones G, P Willett and R C Glen 1995a. A Genetic Algorithm for Flexible Molecular Overlay an Pharmacophore Elucidation. Journal of Computer-Aided Molecular Design 9 532-549. 

Jones G, Willett P, Glen RC. A genetic algorithm for flexible molecular overlay and pharmacophore elucidation. / Comput Aided Mol Des 1995 9(6) 532-49. 

Each of the pharmacophore queries consisted of one donor, one acceptor and one of the two hydrophobic points indicated in Figure 1.16. The directionality of hydrogen bonds was inferred from the X-ray structure and reasonably loose tolerances of 1.5 A were used for donor-acceptor distances and 2-2.5 A to the hydrophobe were chosen to allow for the flexibility seen across kinase structures and to maximise the diversity amongst the identified fragments. Four pharmacophore queries were completed and the results were combined. The chosen fragments were further filtered by molecular weight (between 150 and 250), 51og P (between 2.5 and —2.5) and the presence of... 

Joseph-mccarthy, D., Thomas iv, B.E., Belmarsh, M., Moustakas, D., and Alvarez, J.C. Pharmacophore-based molecular docking to account for ligand flexibility. Proteins Struc., Func. Genet. 

Hindle, S.A., Rarey, M., Buning, C., Len-gauer, T. Flexible docking under pharmacophore constraints. Journal of Computer-Aided Molecular Design 2002, 16, 129-149. 

Algorithm for Flexible Molecular Overlay and Pharmacophore Elucidation. 

---