RESUMO
Receptor-dependent four-dimensional quantitative structure-activity relationship (RD-4D-QSAR) studies were applied on a series of 21 peptides reversible inhibitors of Trypanosoma cruzi trypanothione reductase (TR) (Amino Acids, 20, 2001, 145). The RD-4D-QSAR (J Chem Inform Comp Sci, 43, 2003, 1591) approach can evaluate multiple conformations from molecular dynamics simulation and several superposition structure alignments inside a box composed by unitary cubic cells. The descriptors are the occupancy frequency of the atoms types inside the grid cells. We could develop 3D-QSAR models that were highly predictive (q(2) above 0.71). The 3D-QSAR models can be visualized as a spatial map of atom types that are important on the comprehension of the ligand-enzyme interaction mechanism, pointing main pharmacophoric groups and TR subsites described in the literature. We were able also to identify some TR subsites for further development in the drug discovery process against tropical diseases not yet studied.
Assuntos
Antiparasitários/química , Antiparasitários/farmacologia , NADH NADPH Oxirredutases/antagonistas & inibidores , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Relação Quantitativa Estrutura-Atividade , Trypanosoma cruzi/enzimologia , Doença de Chagas/tratamento farmacológico , Desenho de Fármacos , Humanos , Ligantes , Modelos Moleculares , NADH NADPH Oxirredutases/química , NADH NADPH Oxirredutases/metabolismo , Trypanosoma cruzi/efeitos dos fármacosRESUMO
Drug design is a process driven by innovation and technological breakthroughs involving a combination of advanced experimental and computational methods. A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the optimization of leads into drug candidates. The quantitative structure-activity relationship (QSAR) formalisms are among the most important strategies that can be applied for the successful design new molecules. This review provides a comprehensive review on the evolution and current status of 4D-QSAR, highlighting present challenges and new opportunities in drug design.
Assuntos
Desenho de Fármacos , Relação Quantitativa Estrutura-AtividadeRESUMO
Tuberculosis (TB) is the primary cause of mortality among infectious diseases. Mycobacterium tuberculosis monophosphate kinase (TMPKmt) is essential to DNA replication. Thus, this enzyme represents a promising target for developing new drugs against TB. In the present study, the receptor-independent, RI, 4D-QSAR method has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 81 thymidine analogues, and two corresponding subsets, reported as inhibitors of TMPKmt. The resulting optimized models are not only statistically significant with r(2) ranging from 0.83 to 0.92 and q(2) from 0.78 to 0.88, but also are robustly predictive based on test set predictions. The most and the least potent inhibitors in their respective postulated active conformations, derived from each of the models, were docked in the active site of the TMPKmt crystal structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. Moreover, the QSAR models provide insights regarding a probable mechanism of action of the analogues.
Assuntos
Antituberculosos/química , Inibidores Enzimáticos/química , Mycobacterium tuberculosis/enzimologia , Núcleosídeo-Fosfato Quinase/antagonistas & inibidores , Timidina/análogos & derivados , Algoritmos , Sítios de Ligação/efeitos dos fármacos , Simulação por Computador , Conformação Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Conformação Proteica , Relação Quantitativa Estrutura-Atividade , Tuberculose/tratamento farmacológicoRESUMO
The original quantitative structure-activity relationship (QSAR) formulation was proposed by Hansch and Fujita in the 1960's and, since then QSAR analysis has evolved as a mature science, due mainly to the advances that occurred in the past two decades in the fields of molecular modeling, data analysis algorithms, chemoinformatics, and the application of graph theory in chemistry. Moreover, it is also worthy of note the exponential progress that have occurred in software and hardware development. In this context, a myriad of QSAR methods exist; from the considered "classical" approaches (known as two-dimensional (2D) QSAR), to three-dimensional (3D) and multidimensional (nD) QSAR ones. A distinct QSAR approach has been recently proposed, the receptor-dependent-QSAR, where explicit information regarding the receptor structure (usually a protein) is extensively used during modeling process. Indeed, a limited, but growing number of receptor-dependent QSAR methods are reported in the literature. With no intention to be comprehensive, an overview of receptor-dependent QSAR methods will be discussed along with an in-depth examination of their applications in drug design, virtual screen, and ADMET modeling in silico.
Assuntos
Descoberta de Drogas/métodos , Relação Quantitativa Estrutura-Atividade , Membrana Celular/metabolismo , Análise por Conglomerados , Modelos Moleculares , TermodinâmicaRESUMO
Thymidine monophosphate kinase (TMPK) has emerged as an attractive target for developing inhibitors of Mycobacterium tuberculosis growth. In this study the receptor-independent (RI) 4D-QSAR formalism has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 5'-thiourea-substituted alpha-thymidine inhibitors. Models were developed for the entire training set and for a subset of the training set consisting of the most potent inhibitors. The optimized (RI) 4D-QSAR models are statistically significant (r(2) = 0.90, q(2) = 0.83 entire set, r(2) = 0.86, q(2) = 0.80 high potency subset) and also possess good predictivity based on test set predictions. The most and least potent inhibitors, in their respective postulated active conformations derived from the models, were docked in the active site of the TMPK crystallographic structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. This model identifies new regions of the inhibitors that contain pharmacophore sites, such as the sugar-pyrimidine ring structure and the region of the 5'-arylthiourea moiety. These new regions of the ligands can be further explored and possibly exploited to identify new, novel, and, perhaps, better antituberculosis inhibitors of TMPKmt. Furthermore, the 3D-pharmacophores defined by these models can be used as a starting point for future receptor-dependent antituberculosis drug design as well as to elucidate candidate sites for substituent addition to optimize ADMET properties of analog inhibitors.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Núcleosídeo-Fosfato Quinase/antagonistas & inibidores , Tioureia/química , Timidina/análogos & derivados , Timidina/síntese química , Algoritmos , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Inibidores Enzimáticos/síntese química , Ligantes , Modelos Moleculares , Conformação Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos Testes , Timidina/farmacologiaRESUMO
The p38-mitogen-activated protein kinases (p38-MAPKs) belong to a family of serine-threonine kinases activated by pro-inflammatory or stressful stimuli that are known to be involved in several diseases. Their biological importance, related to the release of inflammatory pro-cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1), has generated many studies aiming at the development of selective inhibitors for the treatment of inflammatory diseases. In this work, we developed receptor-based three dimensional (3D) quantitative structure-activity relationship (QSAR) models for a series of 33 pyridinyl imidazole compounds [Liverton et al. (1999) 42:2180], using a methodology named free-energy force-field (FEFF) [Tokarski and Hopfinger (1997) 37:792], in which scaled intra- and intermolecular energy terms of the Assisted Model Building Energy Refinement (AMBER) force field combined with a hydration-shell solvation model are the independent variables used in the QSAR studies. Multiple temperature molecular-dynamics simulations (MDS) of ligand-protein complexes and genetic-function approximation (GFA) were employed using partial least squares (PLS) as the fitting functions to develop FEFF-3D-QSAR models for the binding process. The best model obtained in the FEFF-3D-QSAR receptor-dependent (RD) method shows the importance of the van der Waals energy change upon binding and the electrostatic energy in the interaction of ligands with the receptor. The QSAR equations described here show good predictability and may be regarded as representatives of the binding process of ligands to p38-MAPK. Additionally, we have compared the top FEFF-3D-QSAR model with receptor independent (RI) 4D-QSAR models developed in a recent study [Romeiro et al. (2005) 19:385].
Assuntos
Imidazóis/química , Inibidores de Proteínas Quinases/química , Relação Quantitativa Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Interações Hidrofóbicas e Hidrofílicas , Imidazóis/farmacologia , Ligantes , Ligação Proteica , Conformação Proteica , Eletricidade Estática , Temperatura , TermodinâmicaRESUMO
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.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Desenho de Fármacos , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/química , Anti-Inflamatórios não Esteroides/farmacologia , Domínio Catalítico , Imidazóis/síntese química , Imidazóis/farmacologia , Conformação Molecular , Piridinas/síntese química , Piridinas/farmacologiaRESUMO
A 4D-QSAR analysis was carried out for a set of 37 hydrazides whose minimum inhibitory concentrations against M. tuberculosis var. bovis were evaluated. These ligands are thought to act like isoniazid in mycolic acid biosynthesis. Results indicate that nonpolar groups in the acyl moiety of ligands markedly decrease biological activity. Molecular modifications of the ligand NAD moiety, including nonpolar groups and hydrogen bond donor and acceptor groups, seemingly improve ligand interactions with amino acid residues of the InhA active site.