Targeting protein conformations with small molecules to control protein complexes

Small molecules can control protein oligomerization by stabilizing or promoting a particular conformational state. Small molecules that turn on and off conformational changes provided important insights into protein function and biological mechanisms. Αdvances in several methodologies enabled the discovery of small-molecule activators and inhibitors of protein conformational changes. A structure-guided drug discovery platform for targeting conformational plasticity of proteins with small-molecule modulators will accelerate the discovery of novel chemical probes and drug candidates in diverse biological mechanisms. Dynamic protein complexes function in all cellular processes, from signaling to transcription, using distinct conformations that regulate their activity. Conformational switching of proteins can turn on or off their activity through protein–protein interactions, catalytic function, cellular localization, or membrane interaction. Recent advances in structural, computational, and chemical methodologies have enabled the discovery of small-molecule activators and inhibitors of conformationally dynamic proteins by using a more rational design than a serendipitous screening approach. Here, we discuss such recent examples, focusing on the mechanism of protein conformational switching and its regulation by small molecules. We emphasize the rational approaches to control protein oligomerization with small molecules that offer exciting opportunities for investigation of novel biological mechanisms and drug discovery. Dynamic protein complexes function in all cellular processes, from signaling to transcription, using distinct conformations that regulate their activity. Conformational switching of proteins can turn on or off their activity through protein–protein interactions, catalytic function, cellular localization, or membrane interaction. Recent advances in structural, computational, and chemical methodologies have enabled the discovery of small-molecule activators and inhibitors of conformationally dynamic proteins by using a more rational design than a serendipitous screening approach. Here, we discuss such recent examples, focusing on the mechanism of protein conformational switching and its regulation by small molecules. We emphasize the rational approaches to control protein oligomerization with small molecules that offer exciting opportunities for investigation of novel biological mechanisms and drug discovery. typically refers to a binding site that is spatially and topologically distinct from orthosteric binding sites. Chemical perturbations by ligands known as allosteric modulators or mutations at allosteric sites can modulate the activity of orthosteric binding sites. combination of chemical and genetic methods commonly used to enhance selectivity and affinity of already existing ligands towards a specific isoform or conformation of the protein target. Typically, this approach relies on protein engineering for the generation of a ‘hole’ in the binding site of ligand, usually by substituting bulky residues with less bulky residues. The ligand is also chemically modified by generating a ‘bump’, which confers steric complementarity for the engineered protein. 3D shape of a protein that is defined by the position of its constituent atoms in space, which arises from the bonding and interactions within the protein structure. all the distinct conformations that a protein can have. Protein molecules are partitioned in several distinct conformations, which are in dynamic equilibrium with each other. ability of a protein to adopt several distinct conformations. phenomenon whereby the affinity of a ligand or a protein subunit toward a protein is increased (positive) or decreased (negative) upon binding of another ligand or protein subunit to the protein, albeit at a spatially distinct binding site. library of structurally distinct small molecules conjugated with a DNA sequence that serves as an identification barcode using high-throughput sequencing. Such libraries commonly find applications in experimental high-throughput screening drug discovery campaigns. ligand or small molecule that binds to the same binding site with an agonist in a constitutively active receptor protein and decreases its activity. computational approach that utilizes algorithms to facilitate pattern recognition and classification based on already existing data with the aim of predicting the likelihood of a particular outcome in a new set of data. It is used in computational biology to generate structural models and drug design. typically refers to a binding site where endogenous ligands and substrates bind. defined spatial orientation of steric and electronic features of a ligand required for the molecular recognition and specific interaction of the ligand with its protein target. Such steric and electronic features include hydrophobic centroids, aromatic rings, hydrogen bond donor/acceptor, anions, and cations. chemical moiety of a small-molecule ligand that can react with amino acids (e.g., cysteine) and form covalent bonds between the protein and the ligand. mathematical function used in protein–ligand docking studies that aims to predict the likelihood of binding for a ligand toward its protein target by evaluating the favorable intermolecular interactions between the ligand and the protein. Scoring functions provide a numerical indicator that is commonly used in in silico screening campaigns to rank different ligands based on their likelihood of binding to the protein target. drug discovery approach that uses the structure of a protein as a starting point and aims to identify ligands that have complementary molecular properties with a specific region of the protein target. Structure-based ligand discovery utilizes in silico methods to virtually screen libraries of compounds or biochemical methods that allow the physical screening of compounds using physicochemical readouts in vitro.