Subject(s)
Adenosine Monophosphate/analogs & derivatives , Polyphosphates , Receptors, Purinergic P2 , Ticlopidine/analogs & derivatives , Uracil Nucleotides , Adenosine/metabolism , Adenosine Diphosphate/metabolism , Adenosine Monophosphate/therapeutic use , Adenosine Triphosphate/metabolism , Animals , Arteriosclerosis/drug therapy , Cloning, Molecular , Clopidogrel , Cystic Fibrosis/drug therapy , Humans , Ophthalmic Solutions/therapeutic use , Receptors, Purinergic P2/chemistry , Receptors, Purinergic P2/metabolism , Structure-Activity Relationship , Ticlopidine/therapeutic use , Tissue DistributionABSTRACT
By using a pharmacophore model, a geometrical representation of the features necessary for molecules to show a particular biological activity, it is possible to search databases containing the 3D structures of molecules and identify novel compounds which may possess this activity. We describe our experiences of establishing a working 3D database system and its use in rational drug design. By using muscarinic M(3) receptor antagonists as an example, we show that it is possible to identify potent novel lead compounds using this approach. Pharmacophore generation based on the structures of known M(3) receptor antagonists, 3D database searching, and medium-throughput screening were used to identify candidate compounds. Three compounds were chosen to define the pharmacophore: a lung-selective M(3) antagonist patented by Pfizer and two Astra compounds which show affinity at the M(3) receptor. From these, a pharmacophore model was generated, using the program DISCO, and this was used subsequently to search a UNITY 3D database of proprietary compounds; 172 compounds were found to fit the pharmacophore. These compounds were then screened, and 1-[2-(2-(diethylamino)ethoxy)phenyl]-2-phenylethanone (pA(2) 6.67) was identified as the best hit, with N-[2-(piperidin-1-ylmethyl)cycohexyl]-2-propoxybenz amide (pA(2) 4. 83) and phenylcarbamic acid 2-(morpholin-4-ylmethyl)cyclohexyl ester (pA(2) 5.54) demonstrating lower activity. As well as its potency, 1-[2-(2-(diethylamino)ethoxy)phenyl]-2-phenylethanone is a simple structure with limited similarity to existing M(3) receptor antagonists.