STACKED – Solvation Theory of Aromatic Complexes as Key for Estimating Drug Binding

Abstract

The use of fragments to biophysically characterize a protein binding pocket and determine the strengths of certain interactions is a computationally and experimentally commonly applied approach. Almost all drug like molecules contain at least one aromatic moiety forming stacking interactions in the binding pocket. In computational drug design, the strength of stacking and the resulting optimization of the aromatic core or moiety is usually calculated using high level quantum mechanical approaches. However, as these calculations are performed in a vacuum, solvation properties are neglected. We close this gap by using Grid Inhomogeneous Solvation Theory (GIST) to describe the properties of individual heteroaromatics and complexes and thereby estimate the desolvation penalty. In our study, we investigated the solvation free energies of heteroaromatics frequently occurring in drug design projects in complex with truncated side chains of phenylalanine, tyrosine, and tryptophan. Furthermore, we investigated the properties of drug-fragments crystallized in a fragment-based lead optimization approach investigating PDE-10-A. We do not only find good correlation for the estimated desolvation penalty and the experimental binding free energy, but our calculations also allow us to predict prominent interaction sites. We highlight the importance of including the desolvation penalty of the respective heteroaromatics in stacked complexes to explain the gain or loss in affinity of potential lead compounds.

COVID-19 Coronavirus spike protein analysis for synthetic vaccines, a peptidomimetic antagonist, and therapeutic drugs, and analysis of a proposed achilles’ heel conserved region to minimize probability of escape mutations and drug resistance

“…Most probably, the binding is sufficiently weak that the normal substrate, and also the spike protein, displace it. Aromatic group interactions may be important here [76]. Organic Compounds Binding the Pharmacophore.…”

“…Of course, many or most drug-like molecules contain at least one aromatic ring and this is almost certainly because they can form especially strong stacking interactions in the binding site. One very relevant report in the same month of writing the present paper emphasizes that the use of protein and other fragments to characterize binding pocket and determine the strengths of ligand-protein interactions is common in both a computational and experimental approach, and that aromatic interactions are both strong and need special attention [76]. Because of resonance and the special nature of the π orbitals, the strength of stacking is best calculated using high level quantum mechanical approaches, not empirical force fields [76].…”

“…One very relevant report in the same month of writing the present paper emphasizes that the use of protein and other fragments to characterize binding pocket and determine the strengths of ligand-protein interactions is common in both a computational and experimental approach, and that aromatic interactions are both strong and need special attention [76]. Because of resonance and the special nature of the π orbitals, the strength of stacking is best calculated using high level quantum mechanical approaches, not empirical force fields [76]. However, as these calculations are performed in vacuum, solvation properties are neglected, and this led to the proposal of a Grid Inhomogeneous Solvation Theory (GIST) to describe the properties of individual heteroaromatics and complexes; this gave good correlation for the estimated desolvation penalty and the experimental binding free energy, and prediction of binding sites [76].…”

“…Because of resonance and the special nature of the π orbitals, the strength of stacking is best calculated using high level quantum mechanical approaches, not empirical force fields [76]. However, as these calculations are performed in vacuum, solvation properties are neglected, and this led to the proposal of a Grid Inhomogeneous Solvation Theory (GIST) to describe the properties of individual heteroaromatics and complexes; this gave good correlation for the estimated desolvation penalty and the experimental binding free energy, and prediction of binding sites [76].…”

Quantum Chemical Microsolvation by Automated Water Placement

“…For example, grid inhomogeneous solvation theory (GIST) allows the analysis and thermodynamic quantification of the solute–solvent interaction on a grid over the whole trajectory [ 42 , 43 ]. Prior studies have shown that GIST can be used to identify favorable interaction sites in heterocycles [ 44 , 45 ] or in biomolecules, [ 43 , 46 , 47 ] for example, in antifreeze proteins [ 47 ] and kinases [ 46 ]. In the latter studies, the grid points were further analyzed to identify positions with high water density to visualize locations of strongly interacting solvent molecules.…”