title: Monitoring the Progression of Structure-Activity Relationship Information during Lead Optimization.
abstract: Lead optimization (LO) in medicinal chemistry is largely driven by hypotheses and depends on the ingenuity, experience, and intuition of medicinal chemists, focusing on the key question of which compound should be made next. It is essentially impossible to predict whether an LO project might ultimately be successful, and it is also very difficult to estimate when a sufficient number of compounds has been evaluated to judge the odds of a project. Given the subjective nature of LO decisions and the inherent optimism of project teams, very few attempts have been made to systematically evaluate project progression. Herein, we introduce a computational framework to follow the evolution of structure-activity relationship (SAR) information over a time course. The approach is based on the use of SAR matrix data structures as a diagnostic tool and enables graphical analysis of SAR redundancy and project progression. This framework should help the process of making decisions in close-in analogue work.
authors.affiliation: Center of Chemistry Innovation & Excellence, WorldWide Medicinal Chemistry, Pfizer PharmaTherapeutics Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Veerabahu
authors.initials: V
authors.lastname: Shanmugasundaram
authors.affiliation: Computational Sciences CoE, WorldWide Medicinal Chemistry, Pfizer PharmaTherapeutics Research & Development , 610 Main Street, Cambridge, Massachusetts 06340, United States.
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Dahlmannstr. 2, Rheinische Friedrich-Wilhelms-Universität, D-53113 Bonn, Germany.
authors.forename: Shilva
authors.initials: S
authors.lastname: Kayastha
authors.affiliation: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Dahlmannstr. 2, Rheinische Friedrich-Wilhelms-Universität, D-53113 Bonn, Germany.
authors.forename: Antonio
authors.initials: A
authors.lastname: de la Vega de León
authors.affiliation: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Dahlmannstr. 2, Rheinische Friedrich-Wilhelms-Universität, D-53113 Bonn, Germany.
authors.forename: Dilyana
authors.initials: D
authors.lastname: Dimova
authors.affiliation: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Dahlmannstr. 2, Rheinische Friedrich-Wilhelms-Universität, D-53113 Bonn, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
mesh_terms: D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D006801:Humans; D013329:Structure-Activity Relationship