Screening of allosteric inhibitors and inhibitors of protein-protein interactions Joel Eggert.

Slides:

Advertisements

Similar presentations

Professor Robin Leatherbarrow Head of Biological Chemistry Department of Chemistry.

Advertisements

Conformational change The enzyme switches back and forth between the two forms. They are in equilibrium. Inactive form Active form Figure 6.19 Allosteric.

Improving Gleevec: Insight from the Receptor Structure Gleevec cannot bind to the open (active) form of the Abl kinase - would collide with open conformation.

Directed Evolution of a Fungal Peroxidase Irene Woo Enzong Yap Joel R. Cherry et al.

Overview of Key ICM Features NIBR - Emeryville July

DRUGGABLE GENOME AND PROTEOME Karen A. Méndez L “the most fruitful basis for the discovery of a new drug is to start with an old drug” (James W Black,

Chemical Biology 1 – Pharmacology Methods for studying protein function – Loss of Function 1. Gene knockouts 2. Conditional knockouts 3. RNAi.

From Chemoinformatics to Systems Chemical Biology Irene Kouskoumvekaki, Associate Professor, Computational Chemical Biology, CBS, DTU-Systems Biology #27803,

Chemical Genomics – Biol503 Lecture 4 Other Applications of Chemical Genomics.

Simon Duri Xixi Hong Joseph Lustig Aleksandra Porebska.

FBDD Advantages? Disadvantages? What is a fragment?

Biol518 Lecture 2 HTS and Antibiotic Drug Discovery.

BACE-1 Inhibitors Alzheimer’s Disease Application of Fragment-Based NMR Screening, X-ray Crystallography, Structure-Based Design, and Focused Chemical.

Design of Small Molecule Drugs Targeted to RNA RNA Ontology Group May

1111 Discovery Novel Allosteric Fragment Inhibitors of HIV-1 Reverse Transcriptase for HIV Prevention A/Prof Gilda Tachedjian Retroviral Biology and Antivirals.

Lecture 4 – the Screening Hypothesis explains why the world goes round!

Integrating Microflow NMR into Fragment-based Drug Discovery Daniel S. Sem Chemical Proteomics Facility at Marquette (CPFM) Department of Chemistry Marquette.

Biol518 Lecture 2 HTS and Antibiotic Drug Discovery.

Structural Bioinformatics R. Sowdhamini National Centre for Biological Sciences Tata Institute of Fundamental Research Bangalore, INDIA.

1 Discovering new drugs in Africa Defeating Malaria Together Kelly Chibale PhD FRSSAf University of Cape Town.

Introduction to Chemoinformatics Irene Kouskoumvekaki Associate Professor December 12th, 2012 Biological Sequence Analysis course.

E. coli Aspartate Transcarbamoylase (ATCase) Wang et al. (2005) Proc Natl Acad Sci USA 102, Macol et al. (2001) Nat Struct Biol 8, Helmstaedt.

DMKPred: Specificity and Cross-reactivity of Kinase Inhibitors

Gleevec vs. BMS Druker vs. Sawyers

Group Red – Demacia Gabe, Chris, Tom. - Enzymes with more than one polypeptide chain can change between an active shape and an inactive shape - When the.

Computer-aided drug discovery (CADD)/design methods have played a major role in the development of therapeutically important small molecules for several.

1 Protein-Protein Interactions High-throughput strategy –Prediction from sequence In silico analysis –Protein A from species A: domain 1 and 2 –Protein.

Introduction to Chemoinformatics and Drug Discovery Irene Kouskoumvekaki Associate Professor February 15 th, 2013.

Enzymes AP Biology. General Information Globular proteins Unique 3 dimensional shape Active site: pocket or groove where substrate binds.

Investigation of the enzymatic processes depending on the type of reaction.

Basic Translational Clinical New Pathways to Discovery Harmonization Target ID & Valid. Phases I-III Research Teams of Future Translational Cores Clinical.

Cloning, Over-expression and Purification of NanoLuc Luciferase

PROTEIN INTERACTION NETWORK – INFERENCE TOOL DIVYA RAO CANDIDATE FOR MASTER OF SCIENCE IN BIOINFORMATICS ADVISOR: Dr. FILIPPO MENCZER CAPSTONE PROJECT.

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Concept 8.4: Enzymes speed up metabolic reactions by lowering energy barriers.

Factors that Affect the Rates of Enzyme catalyzed Reactions [Enzyme] - ↑ [E], ↑ rate [Enzyme] - ↑ [E], ↑ rate [Substrate]- ↑ [S], ↑ rate only up to a point.

Pharmaceutical Approaches to Antiviral Drug Discovery

Molecular Modeling in Drug Discovery: an Overview

Structural Bioinformatics in Drug Discovery Melissa Passino.

Structure-based inhibitor design and validation: Application to Plasmodium falciparum glutathione S-transferase Marli Botha MSc. Bioinformatics.

Structural Bioinformatics Elodie Laine Master BIM-BMC Semester 3, Genomics of Microorganisms, UMR 7238, CNRS-UPMC e-documents:

Pyruvate Dehydrogenase Kinase 4: A potential drug target in non insulin dependent diabetes mellitus Thandeka Khoza.

Page 1 NMR Services —by Creative Biostructure. Page 2 NMR spectroscopy is a key analytical technique for structure elucidation of a wide range of materials.

Page 1 Computer-aided Drug Design —Profacgen. Page 2 The most fundamental goal in the drug design process is to determine whether a given compound will.

Application of High-Throughput Methodology to Human Drug Targets

Nuclear magnetic resonance NMR spectroscopy is a key analytical technique for structure elucidation of a wide range of materials from small molecules to.

Discovery and Development of Medicines

Molecular Docking Profacgen. The interactions between proteins and other molecules play important roles in various biological processes, including gene.

Structural Bioinformatics in Drug Discovery

The Emerging Role of RNA as a Therapeutic Target for Small Molecules

AP Biology Serrano High School

Figure 2 Targeted versus untargeted metabolomics approaches

SB Size: 10 mg M.W.= Batch No.: 1A/ Description:

Figure 1 Therapeutic targeting of the B-cell receptor (BCR)

The increasing availability of quantitative biological data from the human genome project, coupled with advances in instrumentation, reagents, methodologies,

Drug network derived from the core EGFR interactome and combination strategy to overcome the resistant cells. Drug network derived from the core EGFR interactome.

How Chemoproteomics Can Enable Drug Discovery and Development

Allostery in Disease and in Drug Discovery

Living Metabolism Part 2

Expanding the Molecular Toolkit for Chlamydia

Volume 14, Issue 4, Pages (February 2016)

Nat. Rev. Neurol. doi: /nrneurol

Living Metabolism Part 2

Living Metabolism Part 2

Structural mapping of the PLX3397-resistant mutations in FLT3.

Crystal Structure of a Procaspase-7 Zymogen

Living Metabolism Part 2

An isogenic cell line screen reveals genomic drivers of drug response.

Presentation transcript:

Screening of allosteric inhibitors and inhibitors of protein-protein interactions Joel Eggert

Kinase inhibitors Orthosteric Foda & Seeliger, 2014.

Kinase inhibitors OrthostericAllosteric Foda & Seeliger, 2014.

Allosteric inhibitors Advantages – Highly specific – Lower chances of side effects – Overcome clinically acquired resistance – Barely explored

Allosteric inhibitors Disadvantages – Allosteric sites are often unknown – Hard to predict the outcome – Higher divergence between species

High-throughput screen of allosteric inhibitors Goal: identify targets that can stabilize the enzyme in a catalytically inactive conformation

Recombinant cSrc Site-directed mutagenesis + Cys activation loop Acrylodan O/N Mass spec Triplicates: acrylodan-cSrc (100 nM) Compounds: 10 and 50 µM min, RT

Simard et al., 2009

inhibitorbindingkinase Type Iactive siteactive state Type IIactive + allosteric siteinactive state Type IIIallosteric siteinactive state Simard et al., 2009

inhibitorbindingkinase Type Iactive siteactive state Type IIactive + allosteric siteinactive state Type IIIallosteric siteinactive state Simard et al., 2009

inhibitorbindingkinase Type Iactive siteactive state Type IIactive + allosteric siteinactive state Type IIIallosteric siteinactive state Simard et al., 2009

Inhibitors of protein-protein interactions

Chemical library: > compounds ( kDa)

Fragment-screening and fragment- based drug design (FBDD) Low molecular weight compounds NMR Bind – target protein? Weak interactions [mM] Fragment hits Structure-based optimization (fragment linking etc) Lead compound

Sheng et al., 2015

References Foda, Z. H. & Seeliger, M. A. Kinase inhibitors: An allosteric add-on. Nat. Chem. Biol. 10, 796–797 (2014). Nussinov, R. & Tsai, C.-J. Allostery in disease and in drug discovery. Cell 153, 293–305 (2013). Hajduk, P. J. & Greer, J. A decade of fragment-based drug design: strategic advances and lessons learned. Nat. Rev. Drug Discov. 6, 211–219 (2007). Simard, J. R. et al. A new screening assay for allosteric inhibitors of cSrc. Nat. Chem. Biol. 5, 394–396 (2009). Sheng, C., Dong, G., Miao, Z., Zhang, W. & Wang, W. State-of-the-art strategies for targeting protein-protein interactions by small-molecule inhibitors. Chem. Soc. Rev. 44, 8238–8259 (2015).