Predicting where Small Molecules Bind at Protein-Protein Interfaces

Abstract

Small molecules that bind at protein-protein interfaces may either block or stabilize protein-protein interactions in cells. Thus, some of these binding interfaces may turn into prospective targets for drug design. Here, we collected 175 pairs of protein-protein (PP) complexes and protein-ligand (PL) complexes with known three-dimensional structures for which (1) one protein from the PP complex shares at least 40% sequence identity with the protein from the PL complex, and (2) the interface regions of these proteins overlap at least partially with each other. We found that those residues of the interfaces that may bind the other protein as well as the small molecule are evolutionary more conserved on average, have a higher tendency of being located in pockets and expose a smaller fraction of their surface area to the solvent than the remaining protein-protein interface region. Based on these findings we derived a statistical classifier that predicts patches at binding interfaces that have a higher tendency to bind small molecules. We applied this new prediction method to more than 10 000 interfaces from the protein data bank. For several complexes related to apoptosis the predicted binding patches were in direct contact to co-crystallized small molecules.

Dioxygen Binding in the Active Site of Histone Demethylase JMJD2A and the Role of the Protein Environment

“…[47] Ac onductor-like polarizable continuum model (CPCM) with e = 4.3 (diethyl ether as solvent) [48] was applied to mimic the dielectric effects of the relatively hydrophobic protein interior. [49] The B3LYP functional incorporates 20 %e xact HF exchange energy and has been used in the study of oxygen binding to metalloenzymes, with good reproducibility of experimental results. [50] The single-determinant wavefunctions were confirmed to be stable.…”

Covalent Complex of DNA and Bacterial Topoisomerase: Implications in Antibacterial Drug Development

“…[30] It has also been found that some interfacial residues, with higher probability of being pocket residues, have only a smaller fraction of their surface area accessible to solvent and are promising ligand binding sites. [31] Such interfacial interaction [32] may promote the trapping of EctopoIcc by forming a stable ternary complex. The accumulation of these ternary complexes in bacterial cell ultimately may lead to the bacterial cell killing.…”

Considerations of Protein Subpockets in Fragment‐Based Drug Design

“…There have been many studies dealing with the analysis of binding sites, ranging from sequence comparisons, to overall binding site structural similarity and pharmacophore ('fingerprint') searching (8,(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54). Until recently, the majority of the work in the field has looked at the relationship between binding sites in the context of an entire defined pocket.…”