J Chem Inf Model - Structure-based fragment hopping for lead optimization using predocked fragment database.

Tópicos

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Resumo

In this work, we describe a structure-based de novo optimization process, called "LeadOp" (short for lead optimization), that decomposes a compound into fragments of different molecular components either by chemical or user-defined rules. Each fragment is evaluated through a predocked fragment database that ranks fragments according to specific fragment-receptor binding interactions, replacing fragments that contribution the least to binding and finally reassembling the fragments to form a new ligand. The fundamental idea is to replace "bad" fragments of a ligand with "good" fragments while leaving the core of the ligand intact, thus improving the compound's activity. The molecular fragments were selected from a collection of 27,417 conformers that are the fragments of compounds in the DrugBank database. The collection of molecular fragments are docked to the target's binding site and evaluated using group efficiency (calculated binding affinity divided by the number of heavy atoms), and the "strongest" binder is selected. The LeadOp method was tested with two biomolecular systems: mutant B-Raf kinase and human 5-lipoxygenase. The LeadOp methodology was able to optimize the query molecules and systematically developed improved analogs for each of our example systems.

Resumo Limpo

work describ structurebas de novo optim process call leadop short lead optim decompos compound fragment differ molecular compon either chemic userdefin rule fragment evalu predock fragment databas rank fragment accord specif fragmentreceptor bind interact replac fragment contribut least bind final reassembl fragment form new ligand fundament idea replac bad fragment ligand good fragment leav core ligand intact thus improv compound activ molecular fragment select collect conform fragment compound drugbank databas collect molecular fragment dock target bind site evalu use group effici calcul bind affin divid number heavi atom strongest binder select leadop method test two biomolecular system mutant braf kinas human lipoxygenas leadop methodolog abl optim queri molecul systemat develop improv analog exampl system

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