Allen D. Kline

Eli Lilly (United States)

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Huaping Mo

Purdue University West Lafayette

Edward R. Zartler

Pfizer (United States)

Michael J. Shapiro

California Retina Consultants

Jiangli Yan

Yangtze University

Kurt Wüthrich

Scripps Research Institute

Marshall A. Skelton

Eli Lilly (United States)

Cathy S. Harms

Eli Lilly (United States)

Jeffrey T. Mullaney

Eli Lilly (United States)

Werner Braun

The University of Texas Medical Branch at Galveston

Bruce P. Gunn

Bangladesh Medical Research Council

Cooperative Institutions

Eli Lilly (United States)

National Institutes of Health

National Institute of Diabetes and Digestive and Kidney Diseases

Pharmaceutical Product Development (United States)

Indiana University – Purdue University Indianapolis

Indiana University

The Ohio State University

Pfizer (United States)

Eli Lilly (United Kingdom)

University of Wisconsin–Madison

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RAMPED-UP NMR: Multiplexed NMR-Based Screening for Drug Discovery

Journal of the American Chemical Society (2003)

Edward R. Zartler Jeffrey Hanson Bryan E. Jones Allen D. Kline George A. Martin

The crucial step in drug discovery is the identification of a lead compound from a vast chemical library by any number of screening techniques. NMR-based screening has the advantage of directly detecting binding of a compound to the target. The spectra resulting from these screens can also be very complex and difficult to analyze, making this an inefficient process. We present here a method, RAMPED-UP NMR, (Rapid Analysis and Multiplexing of Experimentally Discriminated Uniquely Labeled Proteins using NMR) which generates simple spectra which are easy to interpret and allows several proteins to be screened simultaneously. In this method, the proteins to be screened are uniquely labeled with one amino acid type. There are several benefits derived from this unique labeling strategy: the spectra are greatly simplified, resonances that are most likely to be affected by binding are the only ones observed, and peaks that yield little or no information upon binding are eliminated, allowing the analysis of multiple proteins easily and simultaneously. We demonstrate the ability of three different proteins to be analyzed simultaneously for binding to two different ligands. This method will have significant impact in the use of NMR spectroscopy for both the lead generation and lead optimization phases of drug discovery by its ability to increase screening throughput and the ability to examine selectivity. To the best of our knowledge, this is the first time in any format that multiple proteins can be screened in one tube.

High-Throughput Screening

Proton NMR

Chemical library

10.1021/ja0348593

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Citations (53)

Studies by 1H nuclear magnetic resonance and distance geometry of the solution conformation of the α-amylase inhibitor Tendamistat

Journal of Molecular Biology (1986)

Allen D. Kline Werner Braun Kurt Wüthrich

Nuclear Overhauser effect

Coupling constant

Dihedral angle

10.1016/0022-2836(86)90519-x

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Citations (170)

Comparison of the high-resolution structures of the α-amylase inhibitor tendamistat determined by nuclear magnetic resonance in solution and by X-ray diffraction in single crystals

Journal of Molecular Biology (1989)

Martin Billeter Allen D. Kline Werner Braun Robert Huber Kurt Wüthrich

10.1016/0022-2836(89)90575-5

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Citations (150)

P2‐352: High resolution MRI reveals reduced hippocampal volume in apoE4 targeted replacement mice

Alzheimer s & Dementia (2010)

Jesse M. Hunter Michael D. Cockman Allen D. Kline Scott Surridge Emily C. Rothstein

The epsilon 4 (E4) allele of apolipoprotein E (apoE) is the most significant genetic risk factor for developing late-onset Alzheimer's disease (AD). Cognitively normal apoE4 carriers have altered glucose utilization in brain regions affected in AD as determined by PET. Functional MRI and EEG measurements during memory tasks suggest altered connectivity and broader utilization of brain regions even in young cognitively healthy E4 carriers. E4 is also associated with smaller hippocampal volume and faster rates of atrophy in AD patients. Hippocampal atrophy is also often found in epilepsy. We recently reported the emergence of a seizure phenotype in aged apoE4 targeted replacement (TRE4) mice. To investigate structural brain changes in TRE4 mice, we performed high resolution in vivo MRI of young and aged TR mice with a 7 Tesla Varian spectrometer. Thirty-three slice images (250μm thickness, 98x98μm in-plane resolution, no gap) were acquired for each mouse. Image analysis was performed using custom software or hand drawn regions of interest to determine volumes. All imaging and analysis was done blinded. We report that hippocampal volume is reduced in aged TRE4 mice compared to TRE2 and TRE3 mice. Although young mice do not display a seizure phenotype, young female mice have reduced hippocampal volume and increased ventricular volume suggesting that apoE4 may result in reduced hippocampal development and predisposition to seizures. Seizure phenotype in TRE4 male mice is not completely penetrant, and aged TRE4 male mice with a severe seizure phenotype have reduced hippocampal volume in comparison to aged TRE4 male mice with very mild or no seizure phenotype suggesting a relationship between seizures and hippocampal volume in TRE4 mice. Stereological analysis of the hippocampus of TR mice is in progress and may reveal the cellular basis of the reduced hippocampal volume measured by MRI. Diffusion tensor imaging is also being employed to determine if TRE4 mice have further structural changes detectible by imaging. Our results provide evidence that old and young TRE4 mice have structural brain changes (reduced hippocampal volume) compared to TRE3 or TRE2 mice, suggesting a role for apoE4 in hippocampal integrity and possibly development.

Apolipoprotein E

10.1016/j.jalz.2010.05.1404

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1D NMR Methods in Ligand-Receptor Interactions

Current Topics in Medicinal Chemistry (2003)

Edward R. Zartler Jiangli Yan Huaping Mo Allen D. Kline Michael J. Shapiro

The drug discovery process often involves the screening of compound libraries to identify drug candidates capable of binding to target macromolecules. New approaches in biological and chemical research are driving a change in the pharmaceutical industry. Recent advances in NMR spectroscopy such as affinity NMR techniques, which detect binding of a small molecule with a “receptor”, have been shown to be valuable tools to perform rapid screening of compounds for biological activity. These NMR observable events include using relaxation, chemical shift perturbations, translational diffusion, and magnetization transfer. These one dimensional NMR methods increase both the throughput of screening and yield crucial data on the mode of binding. The practical utility of these techniques will be described. Keywords: NMR Methods, NMR spectroscopy

Chemical shift

10.2174/1568026033392750

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Citations (32)

Monitoring the Ligand Binding Mode by Proton NMR Chemical Shift Differences

ChemMedChem (2006)

Srisunder Subramaniam Steve Briggs Allen D. Kline

The ligand free–bound shift difference is established as a valuable binding mode monitor. Using bovine pancreatic trypsin, an indole inhibitor series and CLEANEX spectroscopy, exchange peaks identified the bound ligand resonances from the free shift positions. The method requires no protein labeling or assignments and is sufficiently fast to be integrated in the drug-design process.

Chemical shift

10.1002/cmdc.200600175

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Citations (1)

ChemInform Abstract: Glutamine‐Derived Aldehydes for the Inhibition of Human Rhinovirus 3C Protease.

ChemInform (1996)

Stephen W. Kaldor M. HAMMOND Bruce A. Dressman Jean M. Labus Frederick W. Chadwell

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Rhinovirus

10.1002/chin.199602249

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Studies by ¹H Nuclear Magnetic Resonance and Distance Geometry of the Solution Conformation of the α-Amylase Inhibitor Tendamistat

World Scientific series in 20th century chemistry (1995)

Allen D. Kline Werner Braun Kurt Wüthrich

Font

10.1142/9789812795830_0027

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Epitope Mapping of Ligand−Receptor Interactions by Diffusion NMR

Journal of the American Chemical Society (2002)

Jiangli Yan Allen D. Kline Huaping Mo Edward R. Zartler Michael J. Shapiro

A novel method based on diffusion NMR for the epitope mapping of ligand binding is presented. The intermolecular NOE builds up during a long diffusion period and creates a deviation from the linearity. The ligand proton nearest the protein generates the strongest NOE from protein during the diffusion period and has the largest deviation. Therefore, this diffusion artifact can be used to characterize the ligand binding epitope. The concept was investigated using dihydrofolate reductase (DHFR) and its ligand trimethoprim (TMP), and the epitope map of TMP on DHFR generated with this method is in excellent agreement with the structural and dynamic studies by crystallography and NMR, as well as the medicinal chemistry results.

Dihydrofolate reductase

10.1021/ja0264347

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Citations (47)

ChemInform Abstract: Dihydroisoquinolone RGD Mimics. Exploration of the Aspartate Isostere.

ChemInform (1998)

M. J. Fisher Bruce P. Gunn Cathy S. Harms Allen D. Kline Jeffrey T. Mullaney

Isostere

10.1002/chin.199804132

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