title: A computational fragment-based de novo design protocol guided by ligand efficiency indices (LEI).
abstract: We present a new protocol aimed at the structure-based design of drug-like molecules using a fragment approach. It starts from a suitably placed and well-defined "base fragment" and then uses an incremental construction algorithm and a scoring function to grow the molecule into prioritized candidates. The selection of the most promising solutions for synthesis and validation is guided by the optimization of the calculated ligand efficiency indices known as binding efficiency index (BEI) and surface efficiency index (SEI), which allow the user to navigate proficiently in chemico-biological space. A test case for the protocol is exemplified here using published data for inhibitors of protein kinase B, aka AKT, a key enzyme in several signal transduction pathways. Our procedure was able to identify the main features responsible for the binding of inhibitors and guided the selection process towards molecules that included or resembled those shown as the most active in the original studies.
authors.affiliation: Unidad de Bioinformática, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Campus de Cantoblanco UAM, Madrid, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Cortés-Cabrera
authors.forename: Federico
authors.initials: F
authors.lastname: Gago
authors.forename: Antonio
authors.initials: A
authors.lastname: Morreale
mesh_terms: D001665:Binding Sites / Q000235:genetics*; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism; D012984:Software
chemical_list: D008024:Ligands; D011506:Proteins; D054852:Small Molecule Libraries; D051057:Proto-Oncogene Proteins c-akt