Desirability-based methods of multiobjective optimization and ranking for global QSAR studies. Filtering safe and potent drug candidates from combinatorial libraries.
Up to now, very few applications of multiobjective optimization (MOOP) techniques to quantitative structure-activity relationship (QSAR) studies have been reported in the literature. However, none of them report the optimization of objectives related directly to the final pharmaceutical profile of a drug. In this paper, a MOOP method based on Derringer's desirability function that allows conducting global QSAR studies, simultaneously considering the potency, bioavailability, and safety of a set of drug candidates, is introduced. The results of the desirability-based MOOP (the levels of the predictor variables concurrently producing the best possible compromise between the properties determining an optimal drug candidate) are used for the implementation of a ranking method that is also based on the application of desirability functions. This method allows ranking drug candidates with unknown pharmaceutical properties from combinatorial libraries according to the degree of similarity with the previously determined optimal candidate. Application of this method will make it possible to filter the most promising drug candidates of a library (the best-ranked candidates), which should have the best pharmaceutical profile (the best compromise between potency, safety and bioavailability). In addition, a validation method of the ranking process, as well as a quantitative measure of the quality of a ranking, the ranking quality index (Psi), is proposed. The usefulness of the desirability-based methods of MOOP and ranking is demonstrated by its application to a library of 95 fluoroquinolones, reporting their gram-negative antibacterial activity and mammalian cell cytotoxicity. Finally, the combined use of the desirability-based methods of MOOP and ranking proposed here seems to be a valuable tool for rational drug discovery and development.
Physico-Chemical Molecular Research Unit, Department of Organic Chemistry, Faculty of Pharmacy, REQUIMTE, Department of Chemistry, and CIQ-UP, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal. gmailkelcm@yahoo.es
Maykel
M
Cruz-Monteagudo
Fernanda
F
Borges
M Natália D S
MN
Cordeiro
J Luis
JL
Cagide Fajin
Carlos
C
Morell
Reinaldo Molina
RM
Ruiz
Yudith
Y
Cañizares-Carmenate
Elena Rosa
ER
Dominguez
D000465:Algorithms; D002470:Cell Survival / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D003625:Data Collection; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D024841:Fluoroquinolones; D006090:Gram-Negative Bacteria / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries
D024841:Fluoroquinolones; D054852:Small Molecule Libraries