title: Probabilistic Approach to Generating MPOs and Its Application as a Scoring Function for CNS Drugs.
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.
authors.affiliation: Department of Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Hakan
authors.initials: H
authors.lastname: Gunaydin
keywords: CNS; MPO; Multiparameter optimization
references.citation: ACS Med Chem Lett. 2012 Nov 06;4(1):108-12
references.pmid: 24900570
references.citation: J Med Chem. 2015 Sep 10;58(17 ):6733-46
references.pmid: 25915084
references.citation: ACS Chem Neurosci. 2010 Jun 16;1(6):435-49
references.pmid: 22778837
references.citation: J Med Chem. 2015 Mar 26;58(6):2584-608
references.pmid: 25494650
references.citation: Pharmacol Rep. 2010 Sep-Oct;62(5):956-65
references.pmid: 21098880
references.citation: Biochemistry. 2006 Mar 7;45(9):3020-32
references.pmid: 16503657
references.citation: Lancet. 1993 Apr 24;341(8852):1054-6
references.pmid: 8096959
references.citation: Expert Opin Drug Metab Toxicol. 2012 May;8(5):531-42
references.pmid: 22458547
references.citation: Nat Chem. 2012 Jan 24;4(2):90-8
references.pmid: 22270643
references.citation: Curr Pharm Des. 2009;15(19):2184-94
references.pmid: 19601822
references.citation: J Med Chem. 2000 Oct 19;43(21):3867-77
references.pmid: 11052792
references.citation: Drug Discov Today. 2010 Aug;15(15-16):648-55
references.pmid: 20570751
references.citation: Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
references.pmid: 11259830