6 research outputs found
Fractal Dimensions of Macromolecular Structures
Quantifying the properties of macromolecules is a prerequisite for understanding their roles in biochemical processes. One of the less-explored geometric features of macromolecules is molecular surface irregularity, or ‘roughness’, which can be measured in terms of fractal dimension (D). In this study, we demonstrate that surface roughness correlates with ligand binding potential. We quantified the surface roughnesses of biological macromolecules in a large-scale survey that revealed D values between 2.0 and 2.4. The results of our study imply that surface patches involved in molecular interactions, such as ligand-binding pockets and protein-protein interfaces, exhibit greater local fluctuations in their fractal dimensions than ‘inert’ surface areas. We expect approximately 22 % of a protein’s surface outside of the crystallographically known ligand binding sites to be ligandable. These findings provide a fresh perspective on macromolecular structure and have considerable implications for drug design as well as chemical and systems biology.ISSN:1868-1743ISSN:1868-175
Targeting Dynamic Pockets of HIV‑1 Protease by Structure-Based Computational Screening for Allosteric Inhibitors
We
present the discovery of low molecular weight inhibitors of
human immunodeficiency virus 1 (HIV-1) protease subtype B that were
identified by structure-based virtual screening as ligands of an allosteric
surface cavity. For pocket identification and prioritization, we performed
a molecular dynamics simulation and observed several flexible, partially
transient surface cavities. For one of these presumable ligand-binding
pockets that are located in the so-called “hinge region”
of the identical protease chains, we computed a receptor-derived pharmacophore
model, with which we retrieved fragment-like inhibitors from a screening
compound pool. The most potent hit inhibited protease activity in
vitro in a noncompetitive mode of action. Although attempts failed
to crystallize this ligand bound to the enzyme, the study provides
proof-of-concept for identifying innovative tool compounds for chemical
biology by addressing flexible protein models with receptor pocket-derived
pharmacophore screening
Recommended from our members