Pharmacophore Point Filter

A Pharmacophore Point Filter contains a set of rules based on medicinal chemistry experience and on the observation that non-drug molecules are often underfunctionalized. Fundamental to this system is evaluating molecules for the occurrence of Pharmacophore Points, functional groups that potentially provide key interaction with the receptor or enzyme. The following rules constitute this filter ... 

In a modified version of the pharmacophore point filter, a score equal to 1 is allowed to qualify a compound as drug-like if the pharmacophore point present in the compound is of type carboxylic acid, amine, guanidine, or amidine. This modified filter was defined to correctly classify the small active drugs belonging to the central nervous system (CNS) class. 

The pharmacophore point filter also includes the following rules ... 

Molecules with less than two and more than seven pharmacophore points fail the filter. 

The requirement of two distinct pharmacophore points neglects at least one very important class of drugs biogenic amine-containing CNS drugs. Therefore, a second pharmacophore filter has been designed that requires only one pharmacophore point in small molecules of the type amine, amidine, guanidine, or carboxylic acid (PF2). 

Gyrase B FRED WDI 7528 (filters Mw, similarity, rotatable bonds, macrocycles removal, steroid-type scaffolds, pharmacophore points, ionization at pH 7) 36 4.1(10) 10 0.41 [109]... 

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... 

Based on an empirical formula, the volume check compares the area (3-point) or volume (4-point) of the potential pharmacophore with the heavy atom count for the molecule. This can exclude pharmacophores that have relatively small size when compared to the molecule size, for example a pharmacophore only involving a single residue in a tetrapeptide molecule. Although the estimate is very approximate, using only the heavy atom count, it appears to be a useful filter. 

The accessibility check eliminates pharmacophores where the putative interacting hydrogen atom or lone pair points within the triangle of the 3-point pharmacophore. The validation of such a filter is less clear, and it has not been used in the reported studies. 

Only geometrical valid distance combinations, checked by the triangle inequality rule, are stored into the final bit string tvhere each bit represents a 4-point pharmacophore, that is, a specific combination of PPP types and geometrical distances. Other two filters, volume check and accessibility check, are applied to select potentially valid pharmacophores. A number of additional filters were also proposed to allow the removal of unwanted pharmacophores, which add noise to the final 4-PPP keys [Good, Cho et al, 2004]. 

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