Quantifying Intrinsic Specificity: A Potential Complement to Affinity in Drug Screening

Abstract

We report here the investigation of a novel description of specificity in protein-ligand binding based on energy landscape theory. We define a new term, intrinsic specificity ratio (ISR), which describes the level of discrimination in binding free energies of the native basin for a protein-ligand complex from the weaker binding states of the same ligand. We discuss the relationship between the intrinsic specificity we defined here and the conventional definition of specificity. In a docking study of molecules with the enzyme COX-2, we demonstrate a statistical correspondence between ISR value and geometrical shapes of the small molecules binding to COX-2. We further observe that the known selective (nonselective) inhibitors of COX-2 have higher (lower) ISR values. We suggest that intrinsic specificity ratio may be a useful new criterion and a complement to affinity in drug screening and in searching for potential drug lead compounds.

Quantifying the topography of the intrinsic energy landscape of flexible biomolecular recognition

“…In thermodynamics, the strong monotonic correlation between T global b =T global g , which measures the feasibility of the binding-folding, and the energy landscape topography measure Λ global is observed, indicating that a deeper, smoother, and smaller funnel will lead to a stronger functional performance and is related to higher binding specificity (65). In kinetics, with a pure structure-based model, the monotonic decreasing relationship between binding-folding time, which measures the efficiency of the binding-folding, and Λ global is observed, implying that the increasing of the slope and the decreasing of the roughness as well as the size of the energy landscape lead to faster kinetics, which is related to functions of higher efficiency.…”

A Self‐Powered and Reusable Biocomputing Security Keypad Lock System Based on Biofuel Cells

“…The open-circuit potential spectrum here is similar to protein folding and binding energy landscape spectra. In protein folding, [11] binding, [12] and signal transduction, [13] the right sequences of amino acid (or molecules for signal transduction) can form a native functioned state with a significant energy gap separating the native state (or destination for signal transduction) with the rest of the other non-native states. The choice of the right sequences for folding, binding, and signal transduction is from the evolution selection for stable and optimal functions.…”

Incorporating specificity into optimization: evaluation of SPA using CSAR 2014 and CASF 2013 benchmarks

“…However, this neglected the quantification of specificity which is critical for the drug-target recognition. Thermodynamically, highly efficient and specific protein-ligand recognition requires two features, one is the stability which is determined by the affinity; the other is the specificity which discriminates the ''native'' specific binding complexes from the competitive non-specific ones [15][16][17][18][19][20][21][22][23][24][25]. For example, a novel drug is often designed by maximizing the binding selectivity to its specific target receptor and minimizing the binding selectivity to others for avoiding the possible side effects.…”

“…To circumvent the challenge, the concept of intrinsic specificity was proposed to describe the binding specificity [15][16][17]. According to the funnel-like energy landscape of protein-ligand binding [16,17,[30][31][32][33][34][35][36][37], the intrinsic specificity ratio (ISR) was quantified to measure the binding specificity. With the quantifications of both specificity and affinity, a knowledge-based scoring function SPecificity and Affinity (SPA) was developed by optimizing the interactions derived from available ''native'' protein-ligand complexes [26].…”