2010
DOI: 10.1021/ci100258p
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Lead Optimization Using Matched Molecular Pairs: Inclusion of Contextual Information for Enhanced Prediction of hERG Inhibition, Solubility, and Lipophilicity

Abstract: Previous studies of the analysis of molecular matched pairs (MMPs) have often assumed that the effect of a substructural transformation on a molecular property is independent of the context (i.e., the local structural environment in which that transformation occurs). Experiments with large sets of hERG, solubility, and lipophilicity data demonstrate that the inclusion of contextual information can enhance the predictive power of MMP analyses, with significant trends (both positive and negative) being identifie… Show more

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Cited by 121 publications
(147 citation statements)
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References 32 publications
(64 reference statements)
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“…To a certain extent, proposed methodology could be considered as somewhat similar to matched molecular pairs approach (MMPA) [47][48][49] in application to QSAR field. The difference between the property of two related structures, e.g., A-B and A-C, containing the common fragment A is explained by the difference in the structure of fragments B and C. To estimate the influence of B to C transformation, in MMPA one can calculate the difference between observed property values for compounds A-B and A-C or between predicted property values by corresponding QSAR models.…”
Section: Universal Approach For Structural Interpretation Of Qsar Modelsmentioning
confidence: 99%
“…To a certain extent, proposed methodology could be considered as somewhat similar to matched molecular pairs approach (MMPA) [47][48][49] in application to QSAR field. The difference between the property of two related structures, e.g., A-B and A-C, containing the common fragment A is explained by the difference in the structure of fragments B and C. To estimate the influence of B to C transformation, in MMPA one can calculate the difference between observed property values for compounds A-B and A-C or between predicted property values by corresponding QSAR models.…”
Section: Universal Approach For Structural Interpretation Of Qsar Modelsmentioning
confidence: 99%
“…Along these lines, matched molecular pairs have been analysed for the effect against various antitargets, such as CYPs or hERG. [18,21] Generally, a stronger effect was observed for those substituents which have a large influence on lipophilicity (logD). [21] Both for progressive and conservative substituent changes, a significant number of matched molecular pairs without significant effects on the antitarget response has been observed.…”
Section: Discussionmentioning
confidence: 99%
“…Some efficient algorithms for computing MMPs [15,16] and extracting trends from large databases are reported for different molecular properties such as primary activity, liver microsomal stability or other ADMET properties . [14,[17][18][19][20][21][22] We use an in-house implementation based on the algorithm described by Hussain and Rea. [16] Relevant MMPs are further filtered by the substituent size, i.e.…”
Section: Conceptmentioning
confidence: 99%
“…However, we have also made other contributions, e.g., in the application of chemoinformatics techniques to the representation and searching of biological macromolecules such as protein and RNA structures, [71][72][73][74][75] in the analysis of matched molecular pairs [76] and in charting the historical development of chemoinformatics and of its associated literature. [77][78][79][80] We have also sought to influence the development of the field by means of conferences and educational programmes.…”
Section: Other Contributionsmentioning
confidence: 99%