RESUMEN
Efficiently scouting the chemical space is one of the major challenges for lead discovery for drug development. In recent times some shifts have been made away from HTS and combinatorial chemistry to more focused approaches. Combinatorial chemistry was the starting point for the development of synthesis concepts that were intended to cover and explore the chemical space without having to prepare every individual compound. In this review, these lead finding approaches will be discussed comparing virtual and synthesized libraries. In addition we discuss the concepts and relationships of evolutionary libraries using genetic algorithms and dynamic combinatorial chemistries, as well as templated fragment ligation concepts. Taking a more abstract view of all approaches, the concepts may loop back into Combinatorial Chemistry allowing a more educated choice of building blocks and chemistries.
Asunto(s)
Técnicas Químicas Combinatorias , Diseño de Fármacos , Industria Farmacéutica , Fragmentos de Péptidos/síntesis química , Biblioteca de PéptidosRESUMEN
The goal of this study was to explore the applicability of surface plasmon resonance (SPR)-based fragment screening to identify compounds that bind to factor VIIa (FVIIa). Based on pharmacophore models virtual screening approaches, we selected fragments anticipated to have a reasonable chance of binding to the S1-binding pocket of FVIIa and immobilized these compounds on microarrays. In affinity fingerprinting experiments, a number of compounds were identified to be specifically interacting with FVIIa and shown to fall into four structural classes. The results demonstrate that the chemical microarray technology platform using SPR detection generates unique chemobiological information that is useful for de novo discovery and lead development and allows the detection of weak interactions with ligands of low molecular weight.
Asunto(s)
Diseño de Fármacos , Factor VIIa/antagonistas & inhibidores , Factor VIIa/metabolismo , Compuestos Orgánicos/química , Péptidos/química , Péptidos/síntesis química , Análisis por Matrices de Proteínas , Química Farmacéutica , Técnicas Químicas Combinatorias , Factor VIIa/química , Ligandos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Peso Molecular , Compuestos Orgánicos/síntesis química , Unión Proteica , Resonancia por Plasmón de SuperficieRESUMEN
The amidinophenylurea scaffold was earlier shown to provide an excellent template for the synthesis of novel and potent inhibitors of the blood coagulation factor VIIa. In this contribution we describe the structure-based design of potent ligands guided by X-ray crystallography, molecular modeling and docking studies. The design and synthetic efforts were directed towards novel modifications to explore the protease binding region close to the S4 subsite.
Asunto(s)
Diseño de Fármacos , Factor VIIa/antagonistas & inhibidores , Fibrinolíticos/síntesis química , Compuestos de Fenilurea/síntesis química , Sitios de Unión , Cristalografía por Rayos X , Factor VIIa/metabolismo , Fibrinolíticos/farmacología , Estructura Molecular , Péptido Hidrolasas/metabolismo , Compuestos de Fenilurea/farmacologíaRESUMEN
A series of novel, highly potent, achiral factor Xa inhibitors based on a benzoic acid scaffold and containing a chlorophenethyl moiety directed towards the protease S1 pocket is described. A number of structural features, such as the requirements of the P1, P4 and ester-binding pocket ligands were explored with respect to inhibition of factor Xa. Compound 46 was found to be the most potent compound in a series of antithrombotic secondary assays.
Asunto(s)
Benzoatos/farmacología , Inhibidores del Factor Xa , Fibrinolíticos/síntesis química , Benzoatos/síntesis química , Pruebas de Coagulación Sanguínea , Estabilidad de Medicamentos , Fibrinolíticos/farmacología , Humanos , Ligandos , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Unión Proteica , Relación Estructura-ActividadRESUMEN
Selective inhibition of coagulation factor VIIa has recently gained attraction as interesting approach towards antithrombotic treatment. Using parallel synthesis supported by structure-based design and X-ray crystallography, we were able to identify a novel series of amidinophenylurea derivatives with remarkable affinity for factor VIIa. The most potent compound displays a K(i) value of 23 nM for factor VIIa.