Rational Modulator Design By Exploitation of protein–protein Complex Structures

Abstract

The horizon of drug discovery is currently expanding to target and modulate protein–protein interactions (PPIs) in globular proteins and intrinsically disordered proteins that are involved in various diseases. To either interrupt or stabilize PPIs, the 3D structure of target protein–protein (or protein–peptide) complexes can be exploited to rationally design PPI modulators (inhibitors or stabilizers) through structure-based molecular design. In this review, we present an overview of experimental and computational methods that can be used to determine 3D structures of protein–protein complexes. Several approaches including rational and in silico methods that can be applied to design peptides, peptidomimetics and small compounds by utilization of determined 3D protein–protein/peptide complexes are summarized and illustrated.

Structure-Based Stabilization of Non-native Protein–Protein Interactions of Coronavirus Nucleocapsid Proteins in Antiviral Drug Design

“…The use of small molecules to stabilize PPI interfaces has been shown to be a viable approach for the development of new therapeutics. Most compounds created by structure-based design to manipulate the PPI depend on detailed knowledge of the native interacting interfaces. − In contrast, most of the compounds with therapeutic potential that stabilize non-native PPI interfaces were discovered by chance alone . The anti-influenza compound nucleozin was initially discovered using a chemical genetics approach, and its ability to stabilize non-native nucleoprotein oligomers was elucidated much later. , Swinholide A, a cytotoxic marine macrolide, has been known to disrupt the actin cytoskeleton and act as an anticancer agent, but it took ten years to discover that it stabilized G-actin as a non-native homodimer complex. − However, these examples did underscore the importance of hydrophobicity as a crucial factor stabilizing protein–protein and protein–ligand associations .…”

N-glycan–mediated shielding of ADAMTS13 prevents binding of pathogenic autoantibodies in immune-mediated TTP

“…As shown previously 8 and here, II-1 and I-9 can no longer bind to GoF-ADAMTS13. The WT and GoF complexes were used in molecular dynamics simulations (Figure 1C; supplemental Video 1, available on the Blood Web site) 16 to determine the most likely binding pose for II-1 and I-9 by means of binding free energy (BFE) calculation, [17][18][19] and the lowest BFE (highest affinity) for the WT-antigen-autoantibody complex (compared with the GoFantigen-autoantibody complex; Figure 1D). The selected complexes for I-9 and II-1 were further investigated at a residue level on the spacer domain, and a larger epitope landscape was predicted by our models.…”

Deciphering the Lexicon of Protein Targets: A Review on Multifaceted Drug Discovery in the Era of Artificial Intelligence

“…In the context of drug design, understanding protein structure and sequence enables researchers to predict how a drug may interact with its target protein, thus offering the potential for increased specificity and effectiveness in drug development. 8 almost all biological processes, and the dysregulation of these interactions often leads to disease states. Therefore, the ability to modulate these interactions provides a significant opportunity for therapeutic intervention.…”

“…The study of their structures and sequences provides us with invaluable insight into their functionality. In the context of drug design, understanding protein structure and sequence enables researchers to predict how a drug may interact with its target protein, thus offering the potential for increased specificity and effectiveness in drug development . Protein–protein interactions (PPIs) represent another crucial aspect of drug design.…”