Macromolecular Interactions as Drug Targets

Interactions between molecules are central to all cellular processes such as ligand recognition, catalysis, and signal transduction. Not surprisingly, many diseases can be directly linked to aberrant interactions between a pair of molecules, which makes it essential to design drugs that can reverse such malignant biophysical processes. While significant experimental-and-computational scientific effort has been devoted in the past to target individual proteins by small molecules, many protein-protein interactions (PPIs) and protein-nucleic acid interactions (PNIs) with a direct role in abnormal signaling have also recently emerged as drug targets. Although PPIs represent critical therapeutic targets, designing potent inhibitors to directly block such interactions remains significantly challenging. These challenges stem from difficulty in overcoming the binding energy associated with PPIs by a small molecule and targeting the large, relatively featureless interaction interfaces that commonly lack well-defined pockets into which small molecules can be targeted. Therefore, targeting allosteric sites may provide greater specificity and importantly remove the need to compete with the protein binding partner. Specifically, small molecules can be designed to covalently or non-covalently associate with allosteric sites on one protein partner such that specific interacting residues with the other protein partner are perturbed. Examples include covalent inhibitors targeting the interaction between the activated Gα-subunits and the regulators of G-protein signaling (RGS) proteins. However, given the slow off-rate of such inhibitors, there remains a need to design better small molecules that can associate non-covalently and achieve similar level of potency and specificity as their covalent counterparts. Moreover, examples exist where similar inhibitors react very differently with homologous proteins. One hypothesis is that the underlying dynamics of such proteins are likely distinct and may manifest uniquely. Therefore, instead of “structure- based drug design”, a novel “dynamics-based drug design” approach is warranted for targeting macromolecular interactions.


In this Frontiers Research Topic, we aim to provide novel insights into the nature of macromolecular interactions (protein-protein/protein-DNA/protein-RNA) using small molecules as chemical probes. We encourage experimental and computational researchers working in the broad area of “small molecule drug design” to contribute high-impact results of their cutting-edge work. Of particular interest are novel computational approaches that go beyond conventional methods and incorporate experimental data to elucidate conformational dynamics of biomolecules. The topic would then include (but not be limited to) studies involving new drug targets, novel inhibitors of macromolecular interactions, new and improved computational algorithms for docking, ligand binding, and thermodynamic property calculation, unique approaches for discovering druggable pockets on biomolecules, peptide or peptide-mimetic inhibitors, allosteric inhibitors, and other novel strategies for target PPIs.