Drug discovery for neglected tropical diseases must use efficient methods due to limited resources. One preferred drug discovery strategy is target-based drug discovery. In this strategy it is assumed that drug action begins with binding of a drug to its target. However, while binding is required, it is not sufficient to describe all the molecular interactions that translate binding to a therapeutically useful pharmacological response. Aspects of a medicine’s molecular mechanism of action (MMOA) such as time-dependence and substrate competition will influence concentration response relationships and the therapeutic index.
To efficiently identify these properties, a four point MMOA methodology was developed and used to characterize inhibitors of Trypanosoma brucei GSK3β inhibitors.T brucei is the parasite responsible for human African trypanosomiasis (also known as African sleeping sickness).Using this method our team identified tideglusib to have a time-dependent, ATP-competitive mechanism that differentiated it from rapidly reversible inhibitors, such as GW8510.
This approach allows for efficient profiling of hits identified in HTS screens for their molecular mechanisms.We employ this strategy at the non-profit Institute for Rare and Neglected Diseases Drug Discovery (www.irnd3.org) to identify new leads and MMOAs for rare and neglected diseases.
Affiliation: Institute for Rare and Neglected Diseases Drug Discovery, Mountain View, California, United States of America
Zachary T. Swinney, Brad A. Haubrich, Shuangluo Xia, Chakk Ramesha, Stephen R. Gomez, Paul Guyett, Kojo Mensa-Wilmot, David C. Swinney. A Four-Point Screening Method for Assessing Molecular Mechanism of Action (MMOA) Identifies Tideglusib as a Time-Dependent Inhibitor of Trypanosoma brucei GSK3β., PLOS Neglected Tropical Diseases Published: March 4, 2016 DOI: 10.1371/journal.pntd.0004506