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Results: 1 to 10 of 120

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Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core.
Tian J, Teuscher KB, Aho ER, Alvarado JR, Mills JJ, Meyers KM, Gogliotti RD, Han C, Macdonald JD, Sai J, Shaw JG, Sensintaffar JL, Zhao B, Rietz TA, Thomas LR, Payne WG, Moore WJ, Stott GM, Kondo J, Inoue M, Coffey RJ, Tansey WP, Stauffer SR, Lee T, Fesik SW
(2020) J Med Chem 63: 656-675
MeSH Terms: Antineoplastic Agents, Bridged Bicyclo Compounds, Heterocyclic, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Chromatin, Crystallography, X-Ray, Drug Design, Drug Discovery, Epigenetic Repression, Genes, myc, Humans, Intracellular Signaling Peptides and Proteins, Quinolones, Structure-Activity Relationship, WD40 Repeats
Show Abstract · Added March 3, 2020
WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple chromatin-centric processes. Overexpression of WDR5 correlates with a poor clinical outcome in many human cancers, and WDR5 itself has emerged as an attractive target for therapy. Most drug-discovery efforts center on the WIN site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe discovery of a novel WDR5 WIN site antagonists containing a dihydroisoquinolinone bicyclic core using a structure-based design. These compounds exhibit picomolar binding affinity and selective concentration-dependent antiproliferative activities in sensitive MLL-fusion cell lines. Furthermore, these WDR5 WIN site binders inhibit proliferation in MYC-driven cancer cells and reduce MYC recruitment to chromatin at MYC/WDR5 co-bound genes. Thus, these molecules are useful probes to study the implication of WDR5 inhibition in cancers and serve as a potential starting point toward the discovery of anti-WDR5 therapeutics.
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16 MeSH Terms
Validation of Human Sterol 14α-Demethylase (CYP51) Druggability: Structure-Guided Design, Synthesis, and Evaluation of Stoichiometric, Functionally Irreversible Inhibitors.
Friggeri L, Hargrove TY, Wawrzak Z, Guengerich FP, Lepesheva GI
(2019) J Med Chem 62: 10391-10401
MeSH Terms: 14-alpha Demethylase Inhibitors, Animals, Catalytic Domain, Crystallography, X-Ray, Drug Design, Humans, Molecular Structure, Mutagenesis, Site-Directed, Protozoan Proteins, Sterol 14-Demethylase
Show Abstract · Added March 3, 2020
Sterol 14α-demethylases (CYP51) are the cytochrome P450 enzymes required for biosynthesis of sterols in eukaryotes, the major targets for antifungal agents and prospective targets for treatment of protozoan infections. Human CYP51 could be and, for a while, was considered as a potential target for cholesterol-lowering drugs (the role that is now played by statins, which are also in clinical trials for cancer) but revealed high intrinsic resistance to inhibition. While microbial CYP51 enzymes are often inhibited stoichiometrically and functionally irreversibly, no strong inhibitors have been identified for human CYP51. In this study, we used comparative structure/functional analysis of CYP51 orthologs from different biological kingdoms and employed site-directed mutagenesis to elucidate the molecular basis for the resistance of the human enzyme to inhibition and also designed, synthesized, and characterized new compounds. Two of them inhibit human CYP51 functionally irreversibly with their potency approaching the potencies of azole drugs currently used to inhibit microbial CYP51.
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10 MeSH Terms
Sign Inversion in Photopharmacology: Incorporation of Cyclic Azobenzenes in Photoswitchable Potassium Channel Blockers and Openers.
Trads JB, Hüll K, Matsuura BS, Laprell L, Fehrentz T, Görldt N, Kozek KA, Weaver CD, Klöcker N, Barber DM, Trauner D
(2019) Angew Chem Int Ed Engl 58: 15421-15428
MeSH Terms: Action Potentials, Azo Compounds, Cyclization, Drug Design, G Protein-Coupled Inwardly-Rectifying Potassium Channels, HEK293 Cells, Humans, Isomerism, Lidocaine, Light, Patch-Clamp Techniques, Potassium Channel Blockers, Thermodynamics
Show Abstract · Added March 27, 2020
Photopharmacology relies on ligands that change their pharmacodynamics upon photoisomerization. Many of these ligands are azobenzenes that are thermodynamically more stable in their elongated trans-configuration. Often, they are biologically active in this form and lose activity upon irradiation and photoisomerization to their cis-isomer. Recently, cyclic azobenzenes, so-called diazocines, have emerged, which are thermodynamically more stable in their bent cis-form. Incorporation of these switches into a variety of photopharmaceuticals could convert dark-active ligands into dark-inactive ligands, which is preferred in most biological applications. This "pharmacological sign-inversion" is demonstrated for a photochromic blocker of voltage-gated potassium channels, termed CAL, and a photochromic opener of G protein-coupled inwardly rectifying potassium (GIRK) channels, termed CLOGO.
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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13 MeSH Terms
BCL::Mol2D-a robust atom environment descriptor for QSAR modeling and lead optimization.
Vu O, Mendenhall J, Altarawy D, Meiler J
(2019) J Comput Aided Mol Des 33: 477-486
MeSH Terms: Algorithms, Drug Design, Drug Discovery, Humans, Ligands, Quantitative Structure-Activity Relationship, Small Molecule Libraries
Show Abstract · Added March 21, 2020
Comparing fragment based molecular fingerprints of drug-like molecules is one of the most robust and frequently used approaches in computer-assisted drug discovery. Molprint2D, a popular atom environment (AE) descriptor, yielded the best enrichment of active compounds across a diverse set of targets in a recent large-scale study. We present here BCL::Mol2D descriptors that outperformed Molprint2D on nine PubChem datasets spanning a wide range of protein classes. Because BCL::Mol2D records the number of AEs from a universal AE library, a novel aspect of BCL::Mol2D over the Molprint2D is its reversibility. This property enables decomposition of prediction from machine learning models to particular molecular substructures. Artificial neural networks with dropout, when trained on BCL::Mol2D descriptors outperform those trained on Molprint2D descriptors by up to 26% in logAUC metric. When combined with the Reduced Short Range descriptor set, our previously published set of descriptors optimized for QSARs, BCL::Mol2D yields a modest improvement. Finally, we demonstrate how the reversibility of BCL::Mol2D enables visualization of a 'pharmacophore map' that could guide lead optimization for serine/threonine kinase 33 inhibitors.
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7 MeSH Terms
HCV Broadly Neutralizing Antibodies Use a CDRH3 Disulfide Motif to Recognize an E2 Glycoprotein Site that Can Be Targeted for Vaccine Design.
Flyak AI, Ruiz S, Colbert MD, Luong T, Crowe JE, Bailey JR, Bjorkman PJ
(2018) Cell Host Microbe 24: 703-716.e3
MeSH Terms: Antibodies, Neutralizing, Antibodies, Viral, Binding Sites, Disulfides, Drug Design, Epitopes, Hepacivirus, Hepatitis C, Hepatitis C Antibodies, Humans, Immunoglobulin G, Models, Molecular, Protein Conformation, Sequence Alignment, Viral Envelope Proteins, Viral Hepatitis Vaccines, X-Ray Diffraction
Show Abstract · Added March 31, 2019
Hepatitis C virus (HCV) vaccine efforts are hampered by the extensive genetic diversity of HCV envelope glycoproteins E1 and E2. Structures of broadly neutralizing antibodies (bNAbs) (e.g., HEPC3, HEPC74) isolated from individuals who spontaneously cleared HCV infection facilitate immunogen design to elicit antibodies against multiple HCV variants. However, challenges in expressing HCV glycoproteins previously limited bNAb-HCV structures to complexes with truncated E2 cores. Here we describe crystal structures of full-length E2 ectodomain complexes with HEPC3 and HEPC74, revealing lock-and-key antibody-antigen interactions, E2 regions (including a target of immunogen design) that were truncated or disordered in E2 cores, and an antibody CDRH3 disulfide motif that exhibits common interactions with a conserved epitope despite different bNAb-E2 binding orientations. The structures display unusual features relevant to common genetic signatures of HCV bNAbs and demonstrate extraordinary plasticity in antibody-antigen interactions. In addition, E2 variants that bind HEPC3/HEPC74-like germline precursors may represent candidate vaccine immunogens.
Copyright © 2018 Elsevier Inc. All rights reserved.
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17 MeSH Terms
De novo designed transmembrane peptides activating the α5β1 integrin.
Mravic M, Hu H, Lu Z, Bennett JS, Sanders CR, Orr AW, DeGrado WF
(2018) Protein Eng Des Sel 31: 181-190
MeSH Terms: Amino Acid Sequence, Cell Membrane, Computer-Aided Design, Drug Design, Humans, Integrin alpha5beta1, Micelles, Peptides, Protein Conformation, alpha-Helical, Protein Domains
Show Abstract · Added November 21, 2018
Computationally designed transmembrane α-helical peptides (CHAMP) have been used to compete for helix-helix interactions within the membrane, enabling the ability to probe the activation of the integrins αIIbβ3 and αvβ3. Here, this method is extended towards the design of CHAMP peptides that inhibit the association of the α5β1 transmembrane (TM) domains, targeting the Ala-X3-Gly motif within α5. Our previous design algorithm was performed alongside a new workflow implemented within the widely used Rosetta molecular modeling suite. Peptides from each computational approach activated integrin α5β1 but not αVβ3 in human endothelial cells. Two CHAMP peptides were shown to directly associate with an α5 TM domain peptide in detergent micelles to a similar degree as a β1 TM peptide does. By solution-state nuclear magnetic resonance, one of these CHAMP peptides was shown to bind primarily the integrin β1 TM domain, which itself has a Gly-X3-Gly motif. The second peptide associated modestly with both α5 and β1 constructs, with slight preference for α5. Although the design goal was not fully realized, this work characterizes novel CHAMP peptides activating α5β1 that can serve as useful reagents for probing integrin biology.
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10 MeSH Terms
Predictive Power of Different Types of Experimental Restraints in Small Molecule Docking: A Review.
Fu DY, Meiler J
(2018) J Chem Inf Model 58: 225-233
MeSH Terms: Algorithms, Drug Design, Drug Discovery, Ligands, Magnetic Resonance Spectroscopy, Molecular Docking Simulation, Proteins, Small Molecule Libraries, Structure-Activity Relationship, User-Computer Interface
Show Abstract · Added March 17, 2018
Incorporating experimental restraints is a powerful method of increasing accuracy in computational protein small molecule docking simulations. Different algorithms integrate distinct forms of biochemical data during the docking and/or scoring stages. These so-called hybrid methods make use of receptor-based information such as nuclear magnetic resonance (NMR) restraints or small molecule-based information such as structure-activity relationships (SARs). A third class of methods directly interrogates contacts between the protein receptor and the small molecule. This work reviews the current state of using such restraints in docking simulations, evaluates their feasibility across broad systems, and identifies potential areas of algorithm development.
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10 MeSH Terms
Principles of Broad and Potent Antiviral Human Antibodies: Insights for Vaccine Design.
Crowe JE
(2017) Cell Host Microbe 22: 193-206
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Antigens, Viral, Antiviral Agents, Cross Reactions, Drug Design, Genes, Reporter, Humans, Immunity, Models, Molecular, Neutralization Tests, Protein Structure, Quaternary, Vaccination, Vaccines, Viral Envelope Proteins, Virus Diseases
Show Abstract · Added March 14, 2018
Antibodies are the principal immune effectors that mediate protection against reinfection following viral infection or vaccination. Robust techniques for human mAb isolation have been developed in the last decade. The study of human mAbs isolated from subjects with prior immunity has become a mainstay for rational structure-based, next-generation vaccine development. The plethora of detailed molecular and genetic studies coupling the structure of antigen-antibody complexes with their antiviral function has begun to reveal common principles of critical interactions on which we can build better vaccines and therapeutic antibodies. This review outlines the approaches to isolating and studying human antiviral mAbs and discusses the common principles underlying the basis for their activity. This review also examines progress toward the goal of achieving a comprehensive understanding of the chemical and physical basis for molecular recognition of viral surface proteins in order to build predictive molecular models that can be used for vaccine design.
Copyright © 2017. Published by Elsevier Inc.
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18 MeSH Terms
Pharmacological targeting of SPAK kinase in disorders of impaired epithelial transport.
Zhang J, Karimy JK, Delpire E, Kahle KT
(2017) Expert Opin Ther Targets 21: 795-804
MeSH Terms: Animals, Colitis, Cystic Fibrosis, Drug Design, Epithelial Cells, Essential Hypertension, Humans, Hypertension, Ion Transport, Molecular Targeted Therapy, Protein-Serine-Threonine Kinases, Signal Transduction
Show Abstract · Added April 3, 2018
INTRODUCTION - The mammalian SPS1-related proline/alanine-rich serine-threonine kinase SPAK (STK39) modulates ion transport across and between epithelial cells in response to environmental stimuli such osmotic stress and inflammation. Research over the last decade has established a central role for SPAK in the regulation of ion and water transport in the distal nephron, colonic crypts, and pancreatic ducts, and has implicated deregulated SPAK signaling in NaCl-sensitive hypertension, ulcerative colitis and Crohn's disease, and cystic fibrosis. Areas covered: We review recent advances in our understanding of the role of SPAK kinase in the regulation of epithelial transport. We highlight how SPAK signaling - including its upstream Cl sensitive activators, the WNK kinases, and its downstream ion transport targets, the cation- Cl cotransporters contribute to human disease. We discuss prospects for the pharmacotherapeutic targeting of SPAK kinase in specific human disorders that feature impaired epithelial homeostasis. Expert opinion: The development of novel drugs that antagonize the SPAK-WNK interaction, inhibit SPAK kinase activity, or disrupt SPAK kinase activation by interfering with its binding to MO25α/β could be useful adjuncts in essential hypertension, inflammatory colitis, and cystic fibrosis.
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Accelerating Precision Drug Development and Drug Repurposing by Leveraging Human Genetics.
Pulley JM, Shirey-Rice JK, Lavieri RR, Jerome RN, Zaleski NM, Aronoff DM, Bastarache L, Niu X, Holroyd KJ, Roden DM, Skaar EP, Niswender CM, Marnett LJ, Lindsley CW, Ekstrom LB, Bentley AR, Bernard GR, Hong CC, Denny JC
(2017) Assay Drug Dev Technol 15: 113-119
MeSH Terms: Databases, Genetic, Drug Design, Drug Repositioning, Genetic Predisposition to Disease, Genome, Human, Humans, Pharmacogenomic Testing, Precision Medicine
Show Abstract · Added April 8, 2017
The potential impact of using human genetic data linked to longitudinal electronic medical records on drug development is extraordinary; however, the practical application of these data necessitates some organizational innovations. Vanderbilt has created resources such as an easily queried database of >2.6 million de-identified electronic health records linked to BioVU, which is a DNA biobank with more than 230,000 unique samples. To ensure these data are used to maximally benefit and accelerate both de novo drug discovery and drug repurposing efforts, we created the Accelerating Drug Development and Repurposing Incubator, a multidisciplinary think tank of experts in various therapeutic areas within both basic and clinical science as well as experts in legal, business, and other operational domains. The Incubator supports a diverse pipeline of drug indication finding projects, leveraging the natural experiment of human genetics.
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8 MeSH Terms