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Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors.
Journal article

Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors.

  • Kuhn B Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
  • Tichý M Laboratorium für Organische Chemie, ETH Zurich , Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
  • Wang L Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
  • Robinson S Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
  • Martin RE Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
  • Kuglstatter A Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
  • Benz J Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
  • Giroud M Laboratorium für Organische Chemie, ETH Zurich , Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
  • Schirmeister T Institut für Pharmazie und Biochemie, Johannes Gutenberg-Universität Mainz , Staudinger Weg 5, 55128 Mainz, Germany.
  • Abel R Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
  • Diederich F Laboratorium für Organische Chemie, ETH Zurich , Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
  • Hert J Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
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  • 2017-03-14
Published in:
  • Journal of medicinal chemistry. - 2017
Binding Sites
Cathepsin L
Drug Design
Enzyme Inhibitors
Halogenation
Humans
Molecular Docking Simulation
Protein Binding
Pyrimidines
Thermodynamics
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/254353
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