title: Desirability-based multiobjective optimization for global QSAR studies: application to the design of novel NSAIDs with improved analgesic, antiinflammatory, and ulcerogenic profiles.
abstract: Up to now, very few reports have been published concerning the application of multiobjective optimization (MOOP) techniques to quantitative structure-activity relationship (QSAR) studies. However, none reports the optimization of objectives related directly to the desired pharmaceutical profile of the drug. In this work, for the first time, it is proposed a MOOP method based on Derringer's desirability function that allows conducting global QSAR studies considering simultaneously the pharmacological, pharmacokinetic and toxicological profile of a set of molecule candidates. The usefulness of the method is demonstrated by applying it to the simultaneous optimization of the analgesic, antiinflammatory, and ulcerogenic properties of a library of fifteen 3-(3-methylphenyl)-2-substituted amino-3H-quinazolin-4-one compounds. The levels of the predictor variables producing concurrently the best possible compromise between these properties is found and used to design a set of new optimized drug candidates. Our results also suggest the relevant role of the bulkiness of alkyl substituents on the C-2 position of the quinazoline ring over the ulcerogenic properties for this family of compounds. Finally, and most importantly, the desirability-based MOOP method proposed is a valuable tool and shall aid in the future rational design of novel successful drugs.
authors.affiliation: Physico-Chemical Molecular Research Unit, Department of Organic Chemistry, Faculty of Pharmacy, University of Porto, 4150-047 Porto, Portugal. gmailkelcm@yahoo.es
authors.forename: Maykel
authors.initials: M
authors.lastname: Cruz-Monteagudo
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
authors.forename: M Natália D S
authors.initials: MN
authors.lastname: Cordeiro
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D015233:Models, Statistical; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D052999:Quinazolinones / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052999:Quinazolinones