title: OOMMPPAA: a tool to aid directed synthesis by the combined analysis of activity and structural data.
abstract: There is an ever increasing resource in terms of both structural information and activity data for many protein targets. In this paper we describe OOMMPPAA, a novel computational tool designed to inform compound design by combining such data. OOMMPPAA uses 3D matched molecular pairs to generate 3D ligand conformations. It then identifies pharmacophoric transformations between pairs of compounds and associates them with their relevant activity changes. OOMMPPAA presents this data in an interactive application providing the user with a visual summary of important interaction regions in the context of the binding site. We present validation of the tool using openly available data for CDK2 and a GlaxoSmithKline data set for a SAM-dependent methyl-transferase. We demonstrate OOMMPPAA's application in optimizing both potency and cell permeability and use OOMMPPAA to highlight nuanced and cross-series SAR. OOMMPPAA is freely available to download at http://oommppaa.sgc.ox.ac.uk/OOMMPPAA/ .
authors.affiliation: SGC, Nuffield Department of Medicine, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Bradley
authors.forename: Ian D
authors.initials: ID
authors.lastname: Wall
authors.forename: Darren V S
authors.initials: DV
authors.lastname: Green
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Deane
authors.forename: Brian D
authors.initials: BD
authors.lastname: Marsden
mesh_terms: D001665:Binding Sites; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D062105:Molecular Docking Simulation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D012436:S-Adenosylmethionine / Q000737:chemistry; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry*; D012984:Software
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D054852:Small Molecule Libraries; D012436:S-Adenosylmethionine; D008780:Methyltransferases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2