Automatic Compound Design by Matched Molecular Pairs
by Willem van Hoorn, Head of Chemoinformatics at Ex Scientia Ltd on Jun 21, 2012
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Matched Molecular Pairs (MMPs) are pairs of molecules that differ by a single structural transformation, which can be due to a chemical reaction but more often involves swapping one chemical group for ...
Matched Molecular Pairs (MMPs) are pairs of molecules that differ by a single structural transformation, which can be due to a chemical reaction but more often involves swapping one chemical group for another in a way that is not feasible in a single synthetic step. It is implicitly understood that in MMPs the static (common) part of the pair is significantly larger than the variable parts. MMPs are popular among medicinal chemists because the concept is closely related to how chemists think about a series of molecules: typically a series is defined as a static core with variable substitutions that each contribute to the overall properties of the molecule like potency, solubility, selectivity, etc. MMPs have been used to mine large sets of biological screening results to answer questions like “how much potency is gained by added a chloro atom in the para postion”. This analysis can be done at multiple levels, for instance all occurrences of the transformation, occurrences against a particular target or occurrences against a target family. For each transformation the average change in potency is recorded which can be used to make quantitative predictions. Suppose a pair of molecules were only the potency of one is known, but the other molecule is related to the first by a single transformation. The predicted potency of the second molecule is the potency of the first plus the average potency change associated with the transformation. Herein lies the power of MMPs compared to classic QSAR regression methods: not only can the potency of novel molecules be predicted but the transformations can be applied as idea generator to come up with reasonable ideas of what the novel molecule(s) should be. In the presentation it is shown how the above can be done using the new MMP algorithm in Pipeline Pilot 8.5 using publicly available datasets from ChEMBL.
(Accelrys European Science Symposium, Brussels, June 2012)
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