Ligand-based combinatorial design of selective purinergic receptor (A2A) antagonists using self-organizing maps.
A virtual screening procedure based on a topological pharmacophore similarity metric and self-organizing maps (SOM) was developed and applied to optimizing combinatorial products functioning as P(1) purinergic receptor antagonists. The target was the human A(2A) receptor. A SOM was developed using a set of biologically tested molecules to establish a preliminary structure-activity relationship. A combinatorial library design was performed by projecting virtually assembled new molecules onto the SOM. A small focused library of 17 selected combinatorial products was synthesized and tested. On average, the designed structures yielded a 3-fold smaller binding constant ( approximately 33 vs approximately 100 nM) and 3.5-fold higher selectivity (50 vs 14) than the initial library. The most selective compound obtained revealed a 121-fold relative selectivity for A(2A) with K(i) (A(2A)) = 2.4 nM, and K(i) (A(1)) = 292 nM. This result demonstrates that it was possible to design a small, activity-enriched focused library with an improved property profile using the SOM virtual screening approach. The strategy might be particularly useful in projects in which structure-based design cannot be applied because of a lack of receptor structure information, for example, in the many projects aiming at finding new GPCR modulators.
F. Hoffmann-La Roche AG, Pharmaceuticals Division, Lead Generation, Grenzacherstrasse 124, CH-4070 Basel, Switzerland. gisbert.schneider@modlab.de
Gisbert
G
Schneider
Matthias
M
Nettekoven
D058917:Adenosine A2 Receptor Antagonists; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry; D011485:Protein Binding; D043705:Receptor, Adenosine A2A / Q000378:metabolism
D058917:Adenosine A2 Receptor Antagonists; D008024:Ligands; D004364:Pharmaceutical Preparations; D043705:Receptor, Adenosine A2A