On the importance of composite protein multiple ligand interactions in protein pockets

Abstract

Conventional small molecule drug-discovery approaches target protein pockets. However, the limited number of geometrically distinct pockets leads to widespread promiscuity and deleterious side-effects. Here, the idea of COmposite protein LIGands (COLIG) that interact with each other as well as the protein within a single ligand binding pocket is examined. As a practical illustration, experimental evidence that E. coli Dihydrofolate reductase inhibitors are COLIGs is presented. Then, analysis of a non-redundant set of all holo PDB structures indicates that almost 47–76% of proteins (based on different sequence identity thresholds) can simultaneously bind multiple, interacting ligands in the same pocket. Moreover, most ligands that are either Singletons and COLIGS bind at the bottom of ligand binding pocket and occupy 30% and 43% of the volume of the bottom of the pocket. This suggests the use of COLIGs as a potential new class of small molecule drugs.

Chemical space of Escherichia coli dihydrofolate reductase inhibitors: New approaches for discovering novel drugs for old bugs

“…This leftward shift is because an increase in substrate concentration in the absence of substrate turnover will push the equilibrium towards the substrate or product bound form of the enzyme that, in turn, is the preferable receptor for the small-molecule inhibitor. In a recent paper from our group, we introduced the concept of COmposite protein LIGands (COLIG) whereby more than one ligand binds to a pocket on the protein’s surface which interact with each other as well as the protein within a single ligand binding pocket 130 . We have also demonstrated, by a systematic analysis of the structures deposited in the Protein data bank (PDB), how uncompetitive kinetics of EcDHFR paves the way for exploration of further cases of uncompetitive inhibition as potential targets of drug discovery 130 .…”

“…In a recent paper from our group, we introduced the concept of COmposite protein LIGands (COLIG) whereby more than one ligand binds to a pocket on the protein’s surface which interact with each other as well as the protein within a single ligand binding pocket 130 . We have also demonstrated, by a systematic analysis of the structures deposited in the Protein data bank (PDB), how uncompetitive kinetics of EcDHFR paves the way for exploration of further cases of uncompetitive inhibition as potential targets of drug discovery 130 . These arguments, coupled with the wide resurgence of interest in targeting allosteric sites for drug discovery 131 , 132 , support the justification for selection of allosteric pockets for drug discovery.…”

Simulating Biomolecules: Festschrift to commemorate the 60th birthday of Charles L. Brooks III

“…[13] Skolnick introduces the concept of COmposite protein LIGands (COLIGs) that are a pair of (or more) ligands that simultaneously interact with each other and the protein pocket, examines its significance, and suggests the use of COLIGs as a potential new class of small molecule drugs. [14] Shen presents conformational dynamics of cathepsin D and binding to a small-molecule BACE1 inhibitor using constant pH molecular dynamics simulations. [15] One way to surmount this difficulty is to find a pair of (or more) ligands that simultaneously interact with each other and the protein pocket; we term such ligands pairs COmposite protein LIGands (COLIGs).…”

“…MacKerell presents relative binding free energy estimations using using pre‐computed ensembles based on the single‐step free energy perturbation and the site‐identification by ligand competitive saturation approaches . Skolnick introduces the concept of COmposite protein LIGands (COLIGs) that are a pair of (or more) ligands that simultaneously interact with each other and the protein pocket, examines its significance, and suggests the use of COLIGs as a potential new class of small molecule drugs . Shen presents conformational dynamics of cathepsin D and binding to a small‐molecule BACE1 inhibitor using constant pH molecular dynamics simulations …”

Pocket detection and interaction-weighted ligand-similarity search yields novel high-affinity binders for Myocilin-OLF, a protein implicated in glaucoma

“…In the first step, Concavity with default parameters 16 identified cavities on Myocilin’s surface and the associated pocket residues were identified. Subsequently, we used APoc 17 to calculate the pocket-pocket similarity between myocilin and the holo pockets of the holo-protein database, PDB-holo (having more than 50,000 entries), used previously 18 ) in order to copy ligands using pocket similarity. A ligand is copied only if the pocket similarity score has a statistically significant p-value (less than 0.01).…”