Assuntos
Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Serina Endopeptidases/metabolismo , Sequência de Aminoácidos , Domínio Catalítico , Células HEK293 , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Modelos Moleculares , Mutagênese Sítio-Dirigida , Mutação , Peptídeos/química , Peptídeos/metabolismo , Serina Endopeptidases/química , Serina Endopeptidases/genética , Especificidade por SubstratoAssuntos
Catepsina B/antagonistas & inibidores , Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Desenho de Fármacos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/farmacologia , Nitrilas/síntese química , Nitrilas/farmacologia , Técnicas de Química Combinatória , Dipeptídeos/química , Humanos , Hidrocarbonetos Fluorados/química , Estrutura Molecular , Nitrilas/química , EstereoisomerismoRESUMO
Discontinuity in structure-activity relationships (SARs) is caused by so-called activity cliffs and represents one of the major caveats in SAR modeling and lead optimization. At activity cliffs, small structural modifications of compounds lead to substantial differences in potency that are essentially unpredictable using quantitative structure-activity relationship (QSAR) methods. In order to better understand SAR discontinuity at the molecular level of detail, we have analyzed different compound series in combinatorial analog graphs and determined substitution patterns that introduce activity cliffs of varying magnitude. So identified SAR determinants were then analyzed on the basis of complex crystal structures to enable a structural interpretation of SAR discontinuity and underlying activity cliffs. In some instances, SAR discontinuity detected within analog series could be well rationalized on the basis of structural data, whereas in others a structural explanation was not possible. This reflects the intrinsic complexity of small molecule SARs and suggests that the analysis of short-range receptor-ligand interactions seen in X-ray structures is insufficient to comprehensively account for SAR discontinuity. However, in other cases, SAR information extracted from ligands was incomplete but could be deduced taking X-ray data into account. Thus, taken together, these findings illustrate the complementarity of ligand-based SAR analysis and structural information.
Assuntos
Descoberta de Drogas/métodos , Técnicas de Química Combinatória , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fator Xa/química , Inibidores do Fator Xa , Modelos Moleculares , Conformação Molecular , Receptor TIE-2/antagonistas & inibidores , Relação Estrutura-Atividade , Trombina/antagonistas & inibidores , Trombina/químicaAssuntos
Anti-Inflamatórios/química , Cianobactérias/química , Elastase de Leucócito/antagonistas & inibidores , Peptídeos Cíclicos/química , Inibidores de Serina Proteinase/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Sítios de Ligação , Simulação por Computador , Humanos , Elastase de Leucócito/metabolismo , Peptídeos Cíclicos/isolamento & purificação , Peptídeos Cíclicos/farmacologia , Inibidores de Serina Proteinase/isolamento & purificação , Inibidores de Serina Proteinase/farmacologiaRESUMO
A methodology is introduced to assign energy-based scores to two-dimensional (2D) structural features based on three-dimensional (3D) ligand-target interaction information and utilize interaction-annotated features in virtual screening. Database molecules containing such fragments are assigned cumulative scores that serve as a measure of similarity to active reference compounds. The Interaction Annotated Structural Features (IASF) method is applied to mine five high-throughput screening (HTS) data sets and often identifies more hits than conventional fragment-based similarity searching or ligand-protein docking.
Assuntos
Simulação por Computador , Avaliação Pré-Clínica de Medicamentos/métodos , Ligantes , Modelos Moleculares , Conformação Molecular , Proteínas/química , DescritoresRESUMO
Similarity searching is often used to preselect compounds for docking, thereby decreasing the size of screening databases. However, integrated structure- and ligand-based screening schemes are rare at present. Docking and similarity search calculations using 2D fingerprints were carried out in a comparative manner on nine target enzymes, for which significant numbers of diverse inhibitors could be obtained. In the absence of knowledge-based docking constraints and target-directed parameter optimisation, fingerprint searching displayed a clear preference over docking calculations. Alternative combinations of docking and similarity search results were investigated and found to further increase compound recall of individual methods in a number of instances. When the results of similarity searching and docking were combined, parallel selection of candidate compounds from individual rankings was generally superior to rank fusion. We suggest that complementary results from docking and similarity searching can be captured by integrated compound selection schemes.