title: Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors.
abstract: Improving the binding affinity of a chemical series by systematically probing one of its exit vectors is a medicinal chemistry activity that can benefit from molecular modeling input. Herein, we compare the effectiveness of four approaches in prioritizing building blocks with better potency: selection by a medicinal chemist, manual modeling, docking followed by manual filtering, and free energy calculations (FEP). Our study focused on identifying novel substituents for the apolar S2 pocket of cathepsin L and was conducted entirely in a prospective manner with synthesis and activity determination of 36 novel compounds. We found that FEP selected compounds with improved affinity for 8 out of 10 picks compared to 1 out of 10 for the other approaches. From this result and other additional analyses, we conclude that FEP can be a useful approach to guide this type of medicinal chemistry optimization once it has been validated for the system under consideration.
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), 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: Laboratorium für Organische Chemie, ETH Zurich , Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
authors.forename: Michal
authors.identifier: 0000-0002-8460-7680
authors.initials: M
authors.lastname: Tichý
authors.affiliation: Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Lingle
authors.identifier: 0000-0002-8170-6798
authors.initials: L
authors.lastname: Wang
authors.affiliation: Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Shaughnessy
authors.initials: S
authors.lastname: Robinson
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Rainer E
authors.identifier: 0000-0001-7895-497X
authors.initials: RE
authors.lastname: Martin
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), 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 (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Benz
authors.affiliation: Laboratorium für Organische Chemie, ETH Zurich , Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
authors.forename: Maude
authors.initials: M
authors.lastname: Giroud
authors.affiliation: Institut für Pharmazie und Biochemie, Johannes Gutenberg-Universität Mainz , Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.affiliation: Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Abel
authors.affiliation: Laboratorium für Organische Chemie, ETH Zurich , Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Diederich
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Jérôme
authors.identifier: 0000-0003-3062-8029
authors.initials: J
authors.lastname: Hert
mesh_terms: D001665:Binding Sites; D056668:Cathepsin L / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D054879:Halogenation; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; D056668:Cathepsin L