Designing ligands to bind proteins.
TLDR
This perspective discusses some of the technical issues - potential functions, protein plasticity, enthalpy/entropy compensation, and others - that contribute, and suggests areas where fundamental understanding of protein-ligand interactions falls short of what is needed.Abstract:
The ability to design drugs (so-called 'rational drug design') has been one of the long-term objectives of chemistry for 50 years. It is an exceptionally difficult problem, and many of its parts lie outside the expertise of chemistry. The much more limited problem - how to design tight-binding ligands (rational ligand design) - would seem to be one that chemistry could solve, but has also proved remarkably recalcitrant. The question is 'Why is it so difficult?' and the answer is 'We still don't entirely know'. This perspective discusses some of the technical issues - potential functions, protein plasticity, enthalpy/entropy compensation, and others - that contribute, and suggests areas where fundamental understanding of protein-ligand interactions falls short of what is needed. It surveys recent technological developments (in particular, isothermal titration calorimetry) that will, hopefully, make now the time for serious progress in this area. It concludes with the calorimetric examination of the association of a series of systematically varied ligands with a model protein. The counterintuitive thermodynamic results observed serve to illustrate that, even in relatively simple systems, understanding protein-ligand association is challenging.read more
Citations
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A Medicinal Chemist’s Guide to Molecular Interactions
TL;DR: This article compile and review the literature on molecular interactions as it pertains to medicinal chemistry through a combination of careful statistical analysis of the large body of publicly available X-ray structure data and experimental and theoretical studies of specific model systems.
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Insights into Protein-Ligand Interactions: Mechanisms, Models, and Methods
Xing Du,Yi Li,Yuan-Ling Xia,Shi-Meng Ai,Shi-Meng Ai,Jing Liang,Peng Sang,Peng Sang,Xing-Lai Ji,Shu-Qun Liu +9 more
TL;DR: The physicochemical mechanisms underlying protein–ligand binding, including the binding kinetics, thermodynamic concepts and relationships, and binding driving forces, are introduced and rationalized.
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Carbonic Anhydrase as a Model for Biophysical and Physical-Organic Studies of Proteins and Protein–Ligand Binding
Vijay M. Krishnamurthy,George K. Kaufman,Adam R. Urbach,Irina Gitlin,Katherine L. Gudiksen,Douglas B. Weibel,George M. Whitesides +6 more
TL;DR: Carbonic anhydrase is a protein that is especially well-suited to serve as a model in many types of studies in biophysics, bioanalysis, the physical-organic chemistry of inhibitor design, and medicinal chemistry.
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Virtual screening: an endless staircase?
TL;DR: Has virtual screening reached its peak?
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The thermodynamics of protein-ligand interaction and solvation: insights for ligand design.
TL;DR: Thermodynamic changes arising from small differences between ligands binding to individual proteins are relatively large and, in general, uncorrelated with changes in solvation, suggesting that trends identified across widely differing proteins are of limited use in explaining or predicting the effects of ligand modifications.
References
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