title: A Pareto Algorithm for Efficient De Novo Design of Multi-functional Molecules.
abstract: We have introduced a Pareto sorting algorithm into Synopsis, a de novo design program that generates synthesizable molecules with desirable properties. We give a detailed description of the algorithm and illustrate its working in 2 different de novo design settings: the design of putative dual and selective FGFR and VEGFR inhibitors, and the successful design of organic structure determining agents (OSDAs) for the synthesis of zeolites. We show that the introduction of Pareto sorting not only enables the simultaneous optimization of multiple properties but also greatly improves the performance of the algorithm to generate molecules with hard-to-meet constraints. This in turn allows us to suggest approaches to address the problem of false positive hits in de novo structure based drug design by introducing structural and physicochemical constraints in the designed molecules, and by forcing essential interactions between these molecules and their target receptor.
authors.affiliation: FD Computing, Stijn Streuvelsstraat 64, 2340, Beerse, Belgium.|Department of Bioengineering, Rice University, 6100 Main Street, Houston, TX, USA.
authors.forename: Frits
authors.initials: F
authors.lastname: Daeyaert
authors.affiliation: Department of Bioengineering, Rice University, 6100 Main Street, Houston, TX, USA.
authors.forename: Micheal W
authors.initials: MW
authors.lastname: Deem
mesh_terms: D000465:Algorithms; D015195:Drug Design; D062105:Molecular Docking Simulation / Q000379:methods*; D021281:Quantitative Structure-Activity Relationship; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D017641:Zeolites / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D017641:Zeolites; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Drug Design; FGFR; OSDAs; Pareto; Receptors; VEGFR; Zeolites; multi-target drugs