Exploration of Fragment Binding Poses Leading to Efficient Discovery of Highly Potent and Orally Effective Inhibitors of FABP4 for Anti-inflammation
- 23 March 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (8), 4090-4106
- https://doi.org/10.1021/acs.jmedchem.9b02107
Abstract
Fatty-acid binding protein 4 (FABP4) is a promising therapeutic target for immunometabolic diseases, while its potential for systemic inflammatory response syndrome treatment has not been explored. Here, a series of 2-(phenylamino)benzoic acids as novel and potent FABP4 inhibitors are rationally designed based on an interesting fragment which adopts multiple binding poses within FABP4. A fusion of these binding poses leads to design of compound 3 with a ~460-fold improvement in binding affinity compared to the initial fragment. A subsequent structure-aided optimization upon 3 results in a promising lead (17) with the highest binding affinity among all the inhibitors, exerting a significant anti-inflammatory effect in cells and effectively attenuating a systemic inflammatory damage in mice. Our work therefore presents a good example of lead compounds discovery derived from the multiple binding poses of a fragment and provides a candidate for development of drugs against inflammation-related diseases.Keywords
Funding Information
- Ministry of Science and Technology of the People's Republic of China (2017YFB0202604, 2018ZX09711002)
- National Natural Science Foundation of China (21807104, 21877122, 81661148046)
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