6533b870fe1ef96bd12cfd75
RESEARCH PRODUCT
Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors.
Maude GiroudRainer E. MartinJérôme HertLingle WangRobert AbelFrançois DiederichAndreas KuglstatterMichal TichýJörg BenzShaughnessy RobinsonTanja SchirmeisterBernd Kuhnsubject
0301 basic medicinePrioritizationMolecular modelHalogenationStereochemistryCathepsin LComputational biology01 natural sciencesMolecular Docking SimulationProspective evaluationCathepsin L03 medical and health sciences0103 physical sciencesDrug DiscoveryHumansEnzyme InhibitorsBinding Sites010304 chemical physicsbiologyChemistryMolecular Docking Simulation030104 developmental biologyPyrimidinesDocking (molecular)Drug Designbiology.proteinMolecular MedicineThermodynamicsProtein Bindingdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2017-03-13 | Journal of medicinal chemistry |