Molecular modeling and QSAR studies of a set of indole and benzimidazole derivatives as H₄ receptor antagonists.
Histamine is an important biogenic amine, which acts with a group of four G-protein coupled receptors (GPCRs), namely H(1) to H(4) (H(1)R - H(4)R) receptors. The actions of histamine at H(4)R are related to immunological and inflammatory processes, particularly in pathophysiology of asthma, and H(4)R ligands having antagonistic properties could be helpful as antiinflammatory agents. In this work, molecular modeling and QSAR studies of a set of 30 compounds, indole and benzimidazole derivatives, as H(4)R antagonists were performed. The QSAR models were built and optimized using a genetic algorithm function and partial least squares regression (WOLF 5.5 program). The best QSAR model constructed with training set (N = 25) presented the following statistical measures: r (2) = 0.76, q (2) = 0.62, LOF = 0.15, and LSE = 0.07, and was validated using the LNO and y-randomization techniques. Four of five compounds of test set were well predicted by the selected QSAR model, which presented an external prediction power of 80%. These findings can be quite useful to aid the designing of new anti-H(4) compounds with improved biological response.
Fernandes
João Paulo S
JP
Laboratório de Planejamento e Síntese de Quimioterápicos Potenciais Contra Endemias Tropicais, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Av. Prof. Lineu Prestes 580, 05508-900 São Paulo, SP, Brazil. jpsfer@usp.br
Pasqualoto
Kerly Fernanda M
KF
Ferreira
Elizabeth I
EI
Brandt
Carlos A
CA
D000465:Algorithms; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000378:metabolism; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology; D001562:Benzimidazoles / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D006632:Histamine / Q000378:metabolism*; D006633:Histamine Antagonists / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism; D016018:Least-Squares Analysis; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D021281:Quantitative Structure-Activity Relationship; D011968:Receptors, Histamine / Q000737:chemistry* / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D001562:Benzimidazoles; D006633:Histamine Antagonists; D007211:Indoles; D011968:Receptors, Histamine; D006632:Histamine