Probabilistic Approach to Generating MPOs and Its Application as a Scoring Function for CNS Drugs

ACS Medicinal Chemistry Letters
Hakan Gunaydin

Abstract

Multiparameter optimization (MPO) scoring functions are popular tools for providing guidance on how to design desired molecules in medicinal chemistry. The utility of a new probabilistic MPO (pMPO) scoring function method and its application as a scoring function for CNS drugs are described in this letter. In this new approach, a minimal number of statistically determined empirical boundaries is combined with the probability distribution of the desired molecules to define desirability functions. This approach attempts to minimize the number of parameters that define MPO scores while maintaining a high level of predictive power. Results obtained from a test-set of orally approved drugs show that the pMPO approach described here can be used to separate desired molecules from undesired ones with accuracy comparable to a Bayesian model with the advantage of better human interpretability. The application of this pMPO approach for blood-brain barrier penetrant drugs is also described.

References

Oct 29, 2000·Journal of Medicinal Chemistry·W J EganJ J Baldwin
Mar 1, 2006·Biochemistry·Ewa Gatlik-LandwojtowiczAnna Seelig
Jul 16, 2009·Current Pharmaceutical Design·Li DiGuy T Carter
Jan 25, 2012·Nature Chemistry·G Richard BickertonAndrew L Hopkins
Mar 31, 2012·Expert Opinion on Drug Metabolism & Toxicology·Travis T WagerPatrick Trapa
Jan 10, 2013·ACS Medicinal Chemistry Letters·Hakan GunaydinYaxiong Sun
Dec 17, 2014·Journal of Medicinal Chemistry·Zoran Rankovic
Apr 29, 2015·Journal of Medicinal Chemistry·Anthony A Estrada, Zachary K Sweeney

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Citations

Mar 19, 2016·ACS Chemical Neuroscience·Travis T WagerAnabella Villalobos
Jan 24, 2017·Drug Discovery Today·Joan Mayol-LlinàsAndrew Ayscough
Apr 5, 2017·Journal of Medicinal Chemistry·Ignacio AliagasMarian C Bryan
Nov 4, 2017·Chemical Communications : Chem Comm·Joan Mayol-LlinàsAdam Nelson
May 1, 2020·Journal of Medicinal Chemistry·Marta SerafiniArmando A Genazzani
Jun 19, 2021·ACS Medicinal Chemistry Letters·Anthony J RoeckerChristopher S Burgey
Jul 25, 2021·Pharmaceutical Research·Sonali S Bharate
Oct 12, 2019·Journal of Medicinal Chemistry·Mayuri GuptaDonald F Weaver
Aug 31, 2021·RSC Medicinal Chemistry·Maximillian Taro William LeeMark David Rackham

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