5MQY

CATHEPSIN L IN COMPLEX WITH 4-[1,3-benzodioxol-5-ylmethyl(2-phenoxyethyl)amino]-5-fluoropyrimidine-2-carbonitrile

Summary for 5MQY

• Entry DOI: 10.2210/pdb5mqy/pdb
• Descriptor: Cathepsin L1, 4-[1,3-benzodioxol-5-ylmethyl(2-phenoxyethyl)amino]-5-fluoropyrimidine-2-carbonitrile, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: protease inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Lysosome: P07711
• Total number of polymer chains: 1
• Total formula weight: 25082.64

Authors

Kuglstatter, A.,Stihle, M.,Benz, J. (deposition date: 2016-12-21, release date: 2017-03-22, Last modification date: 2024-10-16)

Primary citation

Kuhn, B.,Tichy, M.,Wang, L.,Robinson, S.,Martin, R.E.,Kuglstatter, A.,Benz, J.,Giroud, M.,Schirmeister, T.,Abel, R.,Diederich, F.,Hert, J.
Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors.
J. Med. Chem., 60:2485-2497, 2017

PubMed 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.

PubMed: 28287264
DOI: 10.1021/acs.jmedchem.6b01881

Experimental method

X-RAY DIFFRACTION (1.13 Å)