Proteins under pressure: a new way to design drugs!
Proteins under pressure: a new way to design drugs!
The Division of Medicinal Chemistry & Structural Biology recently published the following article in the Journal of Chemical Information and Modeling:
Active Site Pressurization: A New Tool for Structure-Guided Drug Design and Other Studies of Protein Flexibility
Ian M. Withers, Michael P. Mazanetz, Hao Wang, Peter M. Fischer, and Charles A. Laughton
School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, U.K.
Lay summary:
This paper describes the first results from an ongoing collaborative project between our Computational Modelling & Informatics and Medicinal Chemistry groups to improve computer-based methods for drug design. Many of these methods are based on the idea that if you know the shape of the protein (the ‘lock’), you should be able to design the perfect drug (the ‘key’) to fit it. But this does not take into account the experimental observation that as proteins bind drugs, they often change shape in the process, so the correct shape for the ‘key’ is not obvious beforehand. The paper presents an elegant solution to this problem by showing that this induced-fit binding of protein ligands (potential drugs) can be computationally mimicked by simulating the process of injecting a resin into the protein ‘lock’ that expands under pressure and distorts the protein structure as it does so. Snapshots taken at various stages of this process provide models of the protein with distended ligand binding site cavities that potentially provide better drug design start-points than traditional models generated from, for example, X-ray crystal structures.
Click on the title of the publication (above) to see the abstract and full detail