title: A Real-World Perspective on Molecular Design.
abstract: We present a series of small molecule drug discovery case studies where computational methods were prospectively employed to impact Roche research projects, with the aim of highlighting those methods that provide real added value. Our brief accounts encompass a broad range of methods and techniques applied to a variety of enzymes and receptors. Most of these are based on judicious application of knowledge about molecular conformations and interactions: filling of lipophilic pockets to gain affinity or selectivity, addition of polar substituents, scaffold hopping, transfer of SAR, conformation analysis, and molecular overlays. A case study of sequence-driven focused screening is presented to illustrate how appropriate preprocessing of information enables effective exploitation of prior knowledge. We conclude that qualitative statements enabling chemists to focus on promising regions of chemical space are often more impactful than quantitative prediction.
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kuhn
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Guba
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Hert
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Banner
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bissantz
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Simona
authors.initials: S
authors.lastname: Ceccarelli
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Haap
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Körner
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuglstatter
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Lerner
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Patrizio
authors.initials: P
authors.lastname: Mattei
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Werner
authors.initials: W
authors.lastname: Neidhart
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Pinard
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Markus G
authors.initials: MG
authors.lastname: Rudolph
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schulz-Gasch
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Woltering
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Stahl
mesh_terms: D015195:Drug Design; D008968:Molecular Conformation; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D054852:Small Molecule Libraries