J Chem Inf Model - Consensus models of activity landscapes with multiple chemical, conformer, and property representations.

Tópicos

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{ method(1219) similar(1157) match(930) }
{ data(3008) multipl(1320) sourc(1022) }
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{ detect(2391) sensit(1101) algorithm(908) }

Resumo

We report consensus Structure-Activity Similarity (SAS) maps that address the dependence of activity landscapes on molecular representation. As a case study, we characterized the activity landscape of 54 compounds with activities against human cathepsin B (hCatB), human cathepsin L (hCatL), and Trypanosoma brucei cathepsin B (TbCatB). Starting from an initial set of 28 descriptors we selected ten representations that capture different aspects of the chemical structures. These included four 2D (MACCS keys, GpiDAPH3, pairwise, and radial fingerprints) and six 3D (4p and piDAPH4 fingerprints with each including three conformers) representations. Multiple conformers are used for the first time in consensus activity landscape modeling. The results emphasize the feasibility of identifying consensus data points that are consistently formed in different reference spaces generated with several fingerprint models, including multiple 3D conformers. Consensus data points are not meant to eliminate data, disregarding, for example, "true" activity cliffs that are not identified by some molecular representations. Instead, consensus models are designed to prioritize the SAR analysis of activity cliffs and other consistent regions in the activity landscape that are captured by several molecular representations. Systematic description of the SARs of two targets give rise to the identification of pairs of compounds located in the same region of the activity landscape of hCatL and TbCatB suggesting similar mechanisms of action for the pairs involved. We also explored the relationship between property similarity and activity similarity and found that property similarities are suitable to characterize SARs. We also introduce the concept of structure-property-activity (SPA) similarity in SAR studies.

Resumo Limpo

report consensus structureact similar sas map address depend activ landscap molecular represent case studi character activ landscap compound activ human cathepsin b hcatb human cathepsin l hcatl trypanosoma brucei cathepsin b tbcatb start initi set descriptor select ten represent captur differ aspect chemic structur includ four d macc key gpidaph pairwis radial fingerprint six d p pidaph fingerprint includ three conform represent multipl conform use first time consensus activ landscap model result emphas feasibl identifi consensus data point consist form differ refer space generat sever fingerprint model includ multipl d conform consensus data point meant elimin data disregard exampl true activ cliff identifi molecular represent instead consensus model design priorit sar analysi activ cliff consist region activ landscap captur sever molecular represent systemat descript sar two target give rise identif pair compound locat region activ landscap hcatl tbcatb suggest similar mechan action pair involv also explor relationship properti similar activ similar found properti similar suitabl character sar also introduc concept structurepropertyact spa similar sar studi

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