title: Design and Validation of FRESH, a Drug Discovery Paradigm Resting on Robust Chemical Synthesis.
abstract: A method capable of identifying novel synthetic targets for small molecule lead optimization has been developed. The FRESH (FRagment-based Exploitation of modular Synthesis by vHTS) approach relies on a multistep synthetic route to a target series of compounds devised by a close collaboration between synthetic and computational chemists. It combines compound library generation, quantitative structure-acitvity relationship construction, fragment processing, virtual high throughput screening and display of results within the Pipeline Pilot framework. Outcomes enumerate tailored selection of novel synthetic targets with improved potency and optimized physical properties for an emerging compound series. To validate the application of FRESH, three retrospective case studies have been performed to pinpoint reported potent analogues. One prospective case study was performed to demonstrate that FRESH is able to capture additional potent analogues.
authors.affiliation: Department of Chemistry, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Chemistry, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kaiser
authors.affiliation: Department of Chemistry, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Zackery W
authors.initials: ZW
authors.lastname: Dentmon
authors.affiliation: Neurofarba Dept., Sezione di Scienze Farmaceutiche and Laboratorio di Chimica Bioinorganica, Universita degli Studi di Firenze , 50121 Florence, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Ceruso
authors.affiliation: Neurofarba Dept., Sezione di Scienze Farmaceutiche and Laboratorio di Chimica Bioinorganica, Universita degli Studi di Firenze , 50121 Florence, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.affiliation: Neurofarba Dept., Sezione di Scienze Farmaceutiche and Laboratorio di Chimica Bioinorganica, Universita degli Studi di Firenze , 50121 Florence, Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: Department of Chemistry, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
keywords: ADME; FRESH; Pipeline Pilot; QSAR; lead optimization; virtual HTS