RESUMEN
2-Cyano-6-fluorophenylacetamide was explored as a novel P2 scaffold in the design of thrombin inhibitors. Optimization around this structural motif culminated in 14, which is a potent thrombin inhibitor (K(i)=1.2nM) that exhibits robust efficacy in canine anticoagulation and thrombosis models upon oral administration.
Asunto(s)
Acetamidas , Secuencias de Aminoácidos , Anticoagulantes/administración & dosificación , Diseño de Fármacos , Nitrilos , Trombina/antagonistas & inhibidores , Trombosis/tratamiento farmacológico , Acetamidas/síntesis química , Acetamidas/farmacocinética , Acetamidas/uso terapéutico , Administración Oral , Animales , Anticoagulantes/síntesis química , Anticoagulantes/farmacocinética , Sitios de Unión , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Haplorrinos , Humanos , Enlace de Hidrógeno , Modelos Químicos , Nitrilos/síntesis química , Nitrilos/farmacocinética , Nitrilos/uso terapéutico , Ratas , Relación Estructura-ActividadRESUMEN
The state of the art of various computational aspects of docking-based virtual screening of database of small molecules is presented. The review encompasses the different search algorithms and the scoring functions used in docking methods and their applications to protein and nucleic acid drug targets. Recent progress made in the development and application of methods to include target flexibility are summarized. The fundamental issues and challenges involved in comparing various docking methods are discussed. Limitations of current technologies as well as future prospects are presented.
Asunto(s)
Proteínas de la Membrana , Tecnología Farmacéutica/métodos , Tecnología Farmacéutica/tendencias , Algoritmos , Diseño Asistido por Computadora/tendencias , Sistemas de Liberación de Medicamentos/métodos , Ligandos , Unión ProteicaRESUMEN
The performance of several commercially available docking programs is compared in the context of virtual screening. Five different protein targets are used, each with several known ligands. The simulated screening deck comprised 1000 molecules from a cleansed version of the MDL drug data report and 49 known ligands. For many of the known ligands, crystal structures of the relevant protein-ligand complexes were available. We attempted to run experiments with each docking method that were as similar as possible. For a given docking method, hit rates were improved versus what would be expected for random selection for most protein targets. However, the ability to prioritize known ligands on the basis of docking poses that resemble known crystal structures is both method- and target-dependent.
Asunto(s)
Proteínas/química , Relación Estructura-Actividad Cuantitativa , Programas Informáticos , Sitios de Unión , Proteasa del VIH/química , Humanos , Ligandos , Modelos Moleculares , Proteínas Nucleares/química , Unión Proteica , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Proteínas Tirosina Fosfatasas/química , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas c-mdm2 , Trombina/química , Activador de Plasminógeno de Tipo Uroquinasa/químicaRESUMEN
[structure: see text] Oligonucleotides with a novel 2'-O-[2-(guanidinium)ethyl] (2'-O-GE) modification have been synthesized using a novel protecting group strategy for the guanidinium group. This modification enhances the binding affinity of oligonucleotides to RNA as well as duplex DNA (DeltaT(m) 3.2 degrees C per modification). The 2'-O-GE modified oligonucleotides exhibited exceptional resistance to nuclease degradation. The crystal structure of a palindromic duplex formed by a DNA oligonucleotide with a single 2'-O-GE modification was solved at 1.16 A resolution.