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Thermodynamics and Kinetics of Drug Binding

  • Erscheinungsdatum: 09.03.2015
  • Verlag: Wiley-VCH
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Thermodynamics and Kinetics of Drug Binding

This practical reference for medicinal and pharmaceutical chemists combines the theoretical background with modern methods as well as applications from recent lead finding and optimization projects. Divided into two parts on the thermodynamics and kinetics of drug-receptor interaction, the text provides the conceptual and methodological basis for characterizing binding mechanisms for drugs and other bioactive molecules. It covers all currently used methods, from experimental approaches, such as ITC or SPR, right up to the latest computational methods. Case studies of real-life lead or drug development projects are also included so readers can apply the methods learned to their own projects. Finally, the benefits of a thorough binding mode analysis for any drug development project are summarized in an outlook chapter written by the editors. György Keserü obtained his Ph.D. at the University of Budapest (Hungary) and joined Sanofi-Aventis heading a chemistry research lab. In 1999, he moved to Gedeon Richter as the Head of Computer-aided Drug Discovery, being appointed as the Head of Discovery Chemistry in 2007. Since 2003, he also holds a research professorship at the Budapest University of Technology and Economics. His research interests include medicinal chemistry, drug design, and in silico ADME. He has published over 150 papers and more than 10 books and book chapters. Recently he was granted the Prous award by the European Federation of Medicinal Chemistry, EFMC. David Swinney obtained his PhD at the University of Washington in Seattle (USA). He spent 8 years at Syntex Palo Alto before moving on to Roche where he was serving as Department Head of Inflammation and Respiratory Diseases and later as Director of Biochemical Pharmacology. In 2010 he founded the Institute for Rare and Neglected Diseases, which is a non-profit drug discovery organization. Dr. Swinney is an international expert in enzymology and pharmacology with special interest in molecular mechanism of drug action and binding kinetics.


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Thermodynamics and Kinetics of Drug Binding

The Binding Thermodynamics of Drug Candidates

Ernesto Freire
1.1 Affinity Optimization

The affinity optimization of drug candidates is a major goal in drug development. Most often, the starting points for optimization are compounds or fragments identified in screening campaigns. For full-size compounds, the top hits usually have binding affinities in the mid-micromolar range, while for fragments, hits with affinities as weak as millimolar are not uncommon. In both cases, the binding affinity needs to be improved by 5 orders of magnitude or more for a hit to become a reliable drug candidate. Five orders of magnitude improvement in affinity is equivalent to an additional binding energy of -7.0 kcal mol-1 (Delta G = -RT ln(1/ K d)); that is, essentially doubling the binding energy of the starting compound. Performing this task in an efficient way and simultaneously improving or maintaining drug-like properties is not an easy task and, arguably, can be facilitated by an in-depth knowledge of the binding thermodynamics of a compound.

Affinity optimization is not a simple task because it needs to adhere to constraints that maintain or improve the drug-like character of the compound. A common framework is given by the Lipinski rules of five [1, 2], which limit the molecular weight and the number and type of functionalities that are present in the final compound. For screening hits that already have molecular weights around 500, improving the affinity to the required drug levels essentially means doubling the ligand efficiency (LE = Delta G /(number of heavy atoms)). For fragments ( M W - 200), it means that the chemical functionalities that are added to grow the compound must have a better LE than the starting fragment. Furthermore and in addition to binding affinity, other binding-related properties like selectivity or susceptibility to drug-resistant mutations need to be addressed.

Recently, researchers have become aware of the tendency for new drug candidates to be excessively hydrophobic, to exhibit low solubility and poor permeability, and correspondingly exhibit poor drug quality [3]. In order to identify high quality compounds at an early stage or to improve the quality of existing leads, different metrics have been proposed. It has been realized that high quality compounds are those characterized by high potency and simultaneously low hydrophobicity [4]. In fact, if a plot is made of the logarithm of the potency of the compounds versus their ClogP ( Figure 1.1 ) the high quality compounds cluster in the upper left corner. Those compounds are said to have a high lipophilic efficiency (LipE defined as p K d-ClogP; for any given series pIC50 or p K i can also be used in the analysis) [4]. From a fundamental standpoint, an important issue is to assess whether LipE and similar metrics have a solid thermodynamic foundation and how they can be implemented in a prospective way. This is the main topic of this chapter.

Figure 1.1 The logarithm of the binding affinity as a function of ClogP for a series of protease inhibitors analogs. The solid lines represent lines of constant LipE (indicated by the numbers). Compounds with the higher LipE arguably display the best drug-like properties.
1.2 The Binding Affinity

The binding affinity is dictated by the Gibbs energy of binding (Delta G = -RT lnK a or Delta G = -RT ln (1/ K d)), which in turn is the sum of the binding enthalpy (Delta H ) and the binding entropy contribution (- T Delta S ), as shown in Figure 1.2 . The bar graph in Figure 1.2 , is called the thermodynamic signature [5, 6], and provides an instantaneous visual representation of the magnitude of the different interactions that contribute to binding. The thermodynamic signature can be measure

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