Pharmacophore hypothesis

This method represents the most common and traditional application of computational tools to rational drug design. From a list of molecules of known activity, one can establish a 3D-pharmacophore hypothesis that is then transformed into a 3D-search query. This query is then used to search a 3D database for structures that fit the hypothesis within a certain tolerance. If the yield of active molecules is significant, then the query can be used to predict activities on novel compounds. In our situation, the enantiophore is built from the superposition of a list of sample molecules, which are all well separated on a given CSR Hence, the common features of this series of molecules can become a good enantiophore hypothesis for the enantiores-olution on this CSR... 

NMR 3D structure of the undecapeptide U-II generated a ligand pharmacophore hypothesis that served as query for the virtual screening of the Aventis in-house compound repository. Active leads from six different chemical classes could be identihed by the 3D search, for example, compound 17 (ECso = 400nM Fig. 16.2) [91]. 

Dayam R, Sanchez T, Clement O, Shoemaker R, Sei S, Neamati N. P-Diketo acid pharmacophore hypothesis. 1. Discovery of a novel class of HIV-1 integrase inhibitors. J Med Chem 2005 48 111-20. 

A pharmacophore hypothesis can be derived from a series of known ligands and their common 3D-features. The pharmacophore is constructed by superimposing energetically favorable conformations of all ligands according to their consensus in structural features. The template structure for the superposition should fulfill two criteria ... 

The quantitative comparison of the optimized 3D structure of a selected set of ligands allows the development of their minimal 3D structural requirements for the recognition and activation of the biological target, that is, the pharmacophore hypothesis, and gives a sound 3D rationale to the available SARs [21]. A more complete and mechanistically relevant approach to the development of the 3D pharmacophore consists in its translation into a numerical molecular descriptor that quantifies the molecular-pharmacophore similarity-diversity for computational QSAR modeling [21,41]. 

M., Wildgoose, M., Giesing, D., Fravolini, A., Cruciani, G. and Vaz, R.J. (2005) A pharmacophore hypothesis for P-glycoprotein substrate recognition using GRIND-based 3D-QSAR. Journal of Medicinal Chemistry, 48, 2927-2935. 

The CiTest performs the evaluation of the pharmacophore hypothesis computing a non energy-weighted fit value. 

All the above-described methods share in common that the user has to select the calculated hot spots to be considered in the pharmacophore hypothesis. But even without establishing an explicit pharmacophore hypothesis, hot spots can be useful for structure-based drug design. 

Fig. 12.4 Superposition pathway of the glutarimido derivative 11 into the new pharmacophoric hypothesis for a -AR antagonists.

In a paper published in 2000 by Norinder [30], Catalyst was used for the first time to build a common feature pharmacophore hypothesis for HIV-1 protease inhibitors, which was then refined using in-house software (HypoOpt), after having added to it some hundreds of excluded volume spheres. These were actually derived from the X-ray structure of an inhibitor complexed to the enzyme. The aim of the approach was to obtain a computational model with some improved predictive power with respect to the corresponding hypothesis derived without receptor information. 

This section will underline the importance of some of the above-described validation methods depending on the planned use for the pharmacophore model to be determined. It will be illustrated by several case studies. Successful applications are undoubtedly the best way to validate a pharmacophore hypothesis they bring a straightforward answer to the practical question Was the model useful ... 

---