Browsing by Subject "hot spots"

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    A Computational Investigation of Small-Molecule Engagement of Hot Spots at Protein–Protein Interaction Interfaces
    (ACS, 2017-08) Xu, David; Bum-Erdene, Khuchtumur; Si, Yubing; Zhou, Donghui; Liu, Degang; Ghozayel, Mona; Meroueh, Samy; Biochemistry and Molecular Biology, School of Medicine
    The binding affinity of a protein–protein interaction is concentrated at amino acids known as hot spots. It has been suggested that small molecules disrupt protein–protein interactions by either (i) engaging receptor protein hot spots or (ii) mimicking hot spots of the protein ligand. Yet, no systematic studies have been done to explore how effectively existing small-molecule protein–protein interaction inhibitors mimic or engage hot spots at protein interfaces. Here, we employ explicit-solvent molecular dynamics simulations and end-point MM-GBSA free energy calculations to explore this question. We select 36 compounds for which high-quality binding affinity and cocrystal structures are available. Five complexes that belong to three classes of protein–protein interactions (primary, secondary, and tertiary) were considered, namely, BRD4•H4, XIAP•Smac, MDM2•p53, Bcl-xL•Bak, and IL-2•IL-2Rα. Computational alanine scanning using MM-GBSA identified hot-spot residues at the interface of these protein interactions. Decomposition energies compared the interaction of small molecules with individual receptor hot spots to those of the native protein ligand. Pharmacophore analysis was used to investigate how effectively small molecules mimic the position of hot spots of the protein ligand. Finally, we study whether small molecules mimic the effects of the native protein ligand on the receptor dynamics. Our results show that, in general, existing small-molecule inhibitors of protein–protein interactions do not optimally mimic protein–ligand hot spots, nor do they effectively engage protein receptor hot spots. The more effective use of hot spots in future drug design efforts may result in smaller compounds with higher ligand efficiencies that may lead to greater success in clinical trials.
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    Small Molecules Engage Hot Spots through Cooperative Binding To Inhibit a Tight Protein–Protein Interaction
    (ACS, 2017-03) Liu, Degang; Xu, David; Liu, Min; Knabe, William Eric; Yuan, Cai; Zhou, Donghui; Huang, Mingdong; Meroueh, Samy O.; Biochemistry and Molecular Biology, School of Medicine
    Protein–protein interactions drive every aspect of cell signaling, yet only a few small-molecule inhibitors of these interactions exist. Despite our ability to identify critical residues known as hot spots, little is known about how to effectively engage them to disrupt protein–protein interactions. Here, we take advantage of the ease of preparation and stability of pyrrolinone 1, a small-molecule inhibitor of the tight interaction between the urokinase receptor (uPAR) and its binding partner, the urokinase-type plasminogen activator uPA, to synthesize more than 40 derivatives and explore their effect on the protein–protein interaction. We report the crystal structure of uPAR bound to previously discovered pyrazole 3 and to pyrrolinone 12. While both 3 and 12 bind to uPAR and compete with a fluorescently labeled peptide probe, only 12 and its derivatives inhibit the full uPAR·uPA interaction. Compounds 3 and 12 mimic and engage different hot-spot residues on uPA and uPAR, respectively. Interestingly, 12 is involved in a π–cation interaction with Arg-53, which is not considered a hot spot. Explicit-solvent molecular dynamics simulations reveal that 3 and 12 exhibit dramatically different correlations of motion with residues on uPAR. Free energy calculations for the wild-type and mutant uPAR bound to uPA or 12 show that Arg-53 interacts with uPA or with 12 in a highly cooperative manner, thereby altering the contributions of hot spots to uPAR binding. The direct engagement of peripheral residues not considered hot spots through π–cation or salt-bridge interactions could provide new opportunities for enhanced small-molecule engagement of hot spots to disrupt challenging protein–protein interactions.
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    Spatial Regulation of Air Toxics Hot Spots
    (Wiley, 2015) Turaga, Rama Mohana R.; Noonan, Douglas S.; Bostrom, Ann; School of Public and Environmental Affairs
    This paper analyzes the potential implications, in terms of net social costs and distribution of risks and abatement costs, of a policy to address the problem of air toxics “hot spots.” The policy we analyze involves regulation of air toxics sources at increasingly finer spatial resolutions. We develop a model of a decisionmaker choosing emission standards within a net cost minimization framework. Empirical application of the model to two counties in Florida demonstrates that regulation at finer resolutions could involve trade-offs between net social costs and equitable distribution of risks and, in some settings, between individual and population risks.