Thermodynamics of binding interactions in the rational drug design process

Abstract

Modern drug discovery usually involves the rapid screening of large numbers of compounds, either individually or in resolvable mixtures. These compounds may be complex and lead-like or may be small fragments representing optimal scaffolds. Several methods are suitable for detecting binding interactions based on a wide range of different physical platforms. However, the use of thermodynamic measurements has a role to play both in the high-throughput identification of binders and also in the fundamental understanding of molecular interaction, which is central to rational drug design. This review describes the benefits and drawbacks of using thermodynamic characterisation of binding interactions at various stages in the rational drug design process and highlights future opportunities for advances in instrumentation and methodology.

A ‘rule of 0.5’ for the metabolite-likeness of approved pharmaceutical drugs

“…This has therefore led to concepts such as “drug-likeness” (e.g. Empfield and Leeson 2010; Hay et al 2014; Kell 2013; Kola 2008; Kola and Landis 2004; van der Greef and McBurney 2005), “lead-likeness” (Gozalbes and Pineda-Lucena 2011; Holdgate 2007; Oprea et al 2007, 2001; Wunberg et al 2006), and “ligand efficiency” (Hopkins et al 2014) by which the potentially desirable properties of such molecules have been assessed.…”

“…We recognise that any molecule bioactive in human cells (whether as a drug or for purposes of chemical genomics) must cross at least one membrane, that nutrients necessarily do so, that natural products remain a major source of successful (marketed) pharmaceutical drugs (Gozalbes and Pineda-Lucena 2011; Holdgate 2007; Oprea et al 2007, 2001; van Deursen et al 2011; Wunberg et al 2006), and that successful drugs require or at least use membrane transporters (Dobson et al 2009; Dobson and Kell 2008; Giacomini and Huang 2013; Giacomini et al 2010; Kell 2013; Kell and Dobson 2009; Kell et al 2013, 2011; Kell and Goodacre 2014; Lanthaler et al 2011) that normally are used for the transport of intermediary metabolites (Herrgård et al 2008; Swainston et al 2013; Thiele et al 2013). Given the natural role for these transporters as transporters of intermediary metabolites, we and others have thus suggested (hypothesised) that successful drugs are in fact much more like metabolites (we use this term to mean the natural intermediary metabolites of human metabolism, and do not consider metabolites of the drugs) than are the typical structures found in drug discovery libraries (e.g.…”

Identification of Novel Integrin Binding Partners for Calcium and Integrin Binding Protein 1 (CIB1): Structural and Thermodynamic Basis of CIB1 Promiscuity

“…The thermodynamic profiles of CIB1 binding to the various α-integrin CT peptides suggest that the CIB1-integrin interaction is mainly driven by hydrophobic interactions (Fig. 4A) (41). Overall, CIB1 bound to α-integrin CTs with similar stoichiometry, affinity, free energy, and entropy.…”

Affinity-based, biophysical methods to detect and analyze ligand binding to recombinant proteins: Matching high information content with high throughput

“…Understanding the thermodynamics of a molecular interaction is key in drug discovery, as it allows modifications to be made to test compounds in more meaningful way. Thermodynamic measurements are fundamental in trying to understand molecular interaction, and in applying that learning in the pursuit of compounds, not only with higher affinity, but with the appropriate thermodynamic and kinetic profiles for their biological function (Holdgate, 2007). The binding affinity of a test compound is related to the free energy of the interaction, which is dependent upon the enthalpic and entropic components.…”