Homology modeling of the serotonin 5-HT1A receptor using automated docking of bioactive compounds with defined geometry.
This paper describes a rhodopsin-based model of 5-HT(1A) serotonin receptor. The flexibility of the receptor was considered by using large number of models for ligand dockings. Rearrangements of the heptahelical bundle were introduced, which resulted in the improvement of correlation between computational results and experimental data. The model was validated by automated docking of conformationally restricted arylpiperazines. Specific interactions, responsible for the recognition of arylpiperazine derivatives, were identified. An ionic bond was formed between the protonated amine of ligands and Asp3.32. The aromatic moiety and its substituents specifically interacted with Phe6.52 and Ser5.42, respectively, while the carbonyl groups of imide part of ligands formed hydrogen bonds with Asn7.39 and Tyr7.43. The model reproduced the binding affinity of the test group of ligands (correlation r = 0.8 between pK(i) and docking score). It also gave the enrichment in virtual screening-like experiment (100 compounds), in which 34 high-affinity compounds were found among 50 top-scored ligands.
Nowak
Mateusz
M
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Kraków, Poland. nfnowak@cyf-kr.edu.pl
Kołaczkowski
Marcin
M
Pawłowski
Maciej
M
Bojarski
Andrzej J
AJ
D001665:Binding Sites; D003198:Computer Simulation; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry*; D012243:Rhodopsin / Q000737:chemistry; D058829:Serotonin 5-HT1 Receptor Antagonists; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship
D008024:Ligands; D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A; D012243:Rhodopsin