Pharmacophore 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). 

Serotonin 5HT2c agonist 13 Modeller FlexX 530 ChemDiv GPCR library, MW and pharmacophore filtered 5 12.8 lC5o = 20.1nM [25]... 

Neurokinin NKl antagonist 21 Modeller MOBILE FlexX Pharm 11109 leadlike, pharmacophore filtered 1 14.3 — Ki = 251nM [28]... 

Cannabinoid receptor CB2 agonist 18.5 Insight + Gromacs refined Gold 10.340 druglike Maybridge, pharmacophore filtered 1 1.2 pFCso — 5.3 [37]... 

Fatty acid receptor agonist 20.3 NA Glide 70477 diverse, druglike, pharmacophore filtered 1 10 FC5o = 3.6pM [39]... 

Pharmacophore filter did not select any stereoisomers as a rat serum carboxylesterase-enabled ligand... 

At this point it is worth describing in more detail the ways in which pharmacophores may be used in virtual screening. Obviously, in those cases where structural information for the target is lacking, a good pharmacophore model can provide a powerful filter. Indeed, even in cases where structural information is available, it may be worthwhile to apply pharmacophore filters because it greatly reduces the amount of docking required. 

Wolber G, Langer T LigandScout 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. / Chem Inf Model 2005 45 160-9. 

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... 

The 2 pharmacophore models were used to search a database of about 1.8 million compounds assembled from 12 commercial databases. Hypothesis 1 returned approximately 20,000 hits, which were aggressively filtered using the Catalyst scoring function, lack of hit to a hERG pharmacophore, clogP <5, fewer than five donors and ten acceptors. Fifteen compounds remained and were available for... 

Table 6.3 Hit rate and yield from virtual screen of MDDR test set database using both a- A pharmacophores as selection filter [16].

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