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Do enthalpy and entropy distinguish first in class from best in class?
1Department of Biology, Johns Hopkins University, Baltimore, MD 21218, United States. ef@jhu.edu
Drug Discovery Today
|August 16, 2008
Summary
Optimizing drug molecules requires balancing binding enthalpy and entropy. New structure/activity relationship (SAR) methods accelerate this process for improved drug potency.
Area of Science:
- Drug discovery and medicinal chemistry
- Computational chemistry and molecular modeling
- Biophysics and thermodynamics
Background:
- Drug molecule efficacy depends on high-affinity and selective target binding.
- Binding affinity is a composite of binding enthalpy and entropy.
- Optimizing binding enthalpy is challenging, leading to thermodynamically unbalanced drug candidates and suboptimal potency.
Purpose of the Study:
- To highlight the challenges in optimizing binding enthalpy for drug candidates.
- To introduce the growing importance of structure/activity relationships (SARs) that integrate enthalpy-entropy interplay.
- To emphasize the acceleration of drug optimization processes through these advanced SAR approaches.
Main Methods:
- Analysis of thermodynamic contributions to drug-target binding.
- Review of current drug development technologies and their limitations in enthalpic optimization.
- Exploration of emerging SAR methodologies incorporating thermodynamic parameters.
Main Results:
- Current methods often result in drugs with suboptimal potency due to difficulties in enthalpic optimization.
- Enthalpic optimization can be a lengthy process, often requiring multiple product generations.
- New SAR approaches that consider both enthalpy and entropy are gaining traction.
Conclusions:
- Achieving optimal drug potency necessitates a favorable contribution from both binding enthalpy and entropy.
- Advanced SARs that explicitly model the interplay between enthalpy and entropy are crucial for efficient drug design.
- These novel SAR strategies promise to accelerate the optimization of drug candidates, leading to more effective therapeutics.
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