Aromatic interactions at the ligand–protein interface: Implications for the development of docking scoring functions

Abstract

The ability to design and fine-tune non-covalent interactions between organic ligands and proteins is indispensable to rational drug development. Aromatic stacking has long been recognized as one of the key constituents of ligand-protein interfaces. In this communication, we employ a two-parameter geometric model to conduct a large-scale statistical analysis of aromatic contacts in the experimental and computer-generated structures of ligand-protein complexes, considering various combinations of aromatic amino acid residues and ligand rings. The geometry of interfacial π-π stacking in crystal structures accords with experimental and theoretical data collected for simple systems, such as the benzene dimer. Many contemporary ligand docking programs implicitly treat aromatic stacking with van der Waals and Coulombic potentials. Although this approach generally provides a sufficient specificity to model aromatic interactions, the geometry of π-π contacts in high-scoring docking conformations could still be improved. The comprehensive analysis of aromatic geometries at ligand-protein interfaces lies the foundation for the development of type-specific statistical potentials to more accurately describe aromatic interactions in molecular docking. A Perl script to detect and calculate the geometric parameters of aromatic interactions in ligand-protein complexes is available at https://github.com/michal-brylinski/earomatic. The dataset comprising experimental complex structures and computer-generated models is available at https://osf.io/rztha/.

Structure based virtual screening, molecular docking and molecular dynamics simulation of drug like small molecules against cell cycle regulator enzyme FtsZ of Mycobacterium tuberculosis

“…These essential Pi-alkyl bonds were observed in this study. Further the conformational stability of the protein-ligand interactions are derived from Pi-lone, Pi-anion and halogen non covalent interactions (Brylinski 2018;Arthur and Uzairu 2019;Belhassan et al 2019). In this study we observed Pi-sigma interaction in the interface of FtsZ-24284406; Pi-anion bond was observed in FtsZ-49671233 and FtsZ-24791139 complex and one fluorine bond was observed in FtsZ-49671233 complex.…”

In silicodecryption of serotonin–receptor binding: local non-covalent interactions and long-range conformational changes

“…protein-drug complexes and protein/drugnucleic acid complexes, are well known in the literature. [41][42][43][44][45][46] Therefore, a more detailed analysis of these interactions was performed.…”

Computational Evaluation of the Inhibition Efficacies of HIV Antivirals on SARS-CoV-2 (COVID-19) Protease and Identification of 3D Pharmacophore and Hit Compounds

“…In general, the stability of the protein-ligand complex increases with the number of H-bonds for small molecules. However, for drug compounds with large molecular structures and high molecular masses, the stability of the protein-ligand adduct is greatly influenced by alkyl interactions and π -stacking interactions (hydrophobic) in addition to the conventional H-bonds [ 33 , 34 ]. Since the molecular sizes of the anti-HIV drugs are not too low or too high, both H-bond interactions and hydrophobic interactions play a significant role in the receptor-ligand complex formation.…”