title: Construction of 4D-QSAR models for use in the design of novel p38-MAPK inhibitors.
abstract: The p38-mitogen-activated protein kinase (p38-MAPK) plays a key role in lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) release during the inflammatory process, emerging as an attractive target for new anti-inflammatory agents. Four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis [Hopfinger et al., J. Am. Chem. Soc., 119 (1997) 10509] was applied to a series of 33 (a training set of 28 and a test set of 5) pyridinyl-imidazole and pyrimidinyl-imidazole inhibitors of p38-MAPK, with IC50 ranging from 0.11 to 2100 nM [Liverton et al., J. Med. Chem., 42 (1999) 2180]. Five thousand conformations of each analogue were sampled from a molecular dynamics simulation (MDS) during 50 ps at a constant temperature of 303 K. Each conformation was placed in a 2 angstroms grid cell lattice for each of three trial alignments. 4D-QSAR models were constructed by genetic algorithm (GA) optimization and partial least squares (PLS) fitting, and evaluated by leave-one-out cross-validation technique. In the best models, with three to six terms, the adjusted cross-validated squared correlation coefficients, Q2adj, ranged from 0.67 to 0.85. Model D (Q2adj = 0.84) was identified as the most robust model from alignment 1, and it is representative of the other best models. This model encompasses new molecular regions as containing pharmacophore sites, such as the amino-benzyl moiety of pyrimidine analogs and the N1-substituent in the imidazole ring. These regions of the ligands should be further explored to identify better anti-inflammatory inhibitors of p38-MAPK.
authors.affiliation: Departamento de Química Orgânica, Laboratório de Modelagem Molecular (LabMMol), Instituto de Química, Centro de Tecnologia, Bloco A, Ilha do Fundão, Universidade Federal do Rio de Janeiro, 21949-900, Rio de Janeiro, RJ, Brasil. nelilma@far.fiocruz.br
authors.forename: Nelilma Correia
authors.initials: NC
authors.lastname: Romeiro
authors.forename: Magaly Girão
authors.initials: MG
authors.lastname: Albuquerque
authors.forename: Ricardo Bicca
authors.initials: RB
authors.lastname: de Alencastro
authors.forename: Malini
authors.initials: M
authors.lastname: Ravi
authors.forename: Anton J
authors.initials: AJ
authors.lastname: Hopfinger
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D020134:Catalytic Domain; D015195:Drug Design; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007093:Imidazoles; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580