Dispensing Processes Profoundly Impact Biological, Computational and Statistical Analyses
|
|
- Lorin Lee
- 5 years ago
- Views:
Transcription
1 Dispensing Processes Profoundly Impact Biological, Computational and Statistical Analyses Sean Ekins 1, Joe Olechno 2 Antony J. Williams 3 1 Collaborations in Chemistry, Fuquay Varina, NC. 2 Labcyte Inc, Sunnyvale, CA. 3 Royal Society of Chemistry, Wake Forest, NC. Disclaimer: SE and AJW have no affiliation with Labcyte and have not been engaged as consultants
2 Where do scientists get chemistry/ biology data? Databases Patents Papers Your own lab Collaborators If I have seen further than others, it is by standing upon the shoulders of giants. Some or all of the above? What is common to all? quality issues Isaac Newton
3 Data can be found but..drug structure quality is important More groups doing in silico repositioning Target-based or ligand-based Network and systems biology integrating or using sets of FDA drugs..if the structures are incorrect predictions will be too.. Need a definitive set of FDA approved drugs with correct structures Also linkage between in vitro data & clinical data
4 Structure Quality Issues Database released and within days 100 s of errors found in structures Science Translational Medicine 2011 NPC Browser DDT, 16: (2011) DDT 17: (2012)
5 DDT editorial Dec 2011 Its not just structure quality we need to worry about This editorial led to the current work
6 Finding structures of Pharma molecules is hard NCATS and MRC made molecule identifiers from pharmas available with no structures Southan et al., DDT, 18: (2013)
7 How do you move a liquid? Plastic leaching Images courtesy of Bing, Tecan McDonald et al., Science 2008, 322, 917. Belaiche et al., Clin Chem 2009, 55,
8 Moving Liquids with sound: Acoustic Droplet Ejection (ADE) Acoustic energy expels droplets without physical contact Extremely precise Extremely accurate Rapid Auto-calibrating Completely touchless No crosscontamination No leachates No binding %CV Volume (nl) Comley J, Nanolitre Dispensing, Drug Discovery World, Summer 2004, Images courtesy of Labcyte Inc.
9 Using literature data from different dispensing methods to generate computational models Few molecule structures and corresponding datasets are public Using data from 2 AstraZeneca patents Tyrosine kinase EphB4 pharmacophores (Accelrys Discovery Studio) were developed using data for 14 compounds IC 50 determined using different dispensing methods Analyzed correlation with simple descriptors (SAS JMP) Calculated LogP correlation with log IC 50 data for acoustic dispensing (r 2 = 0.34, p < 0.05, N = 14) Barlaam, B. C.; Ducray, R., WO 2009/ A1, 2009 Barlaam, B. C.; Ducray, R.; Kettle, J. G., US 7,718,653 B2, 2010
10 14 compounds with structures and IC 50 data. Compound # IC 50 Acoustic (µm) IC 50 Tips (µm) Ratio IC 50Tip /IC 50ADE W7b W W W W W Barlaam, B. C.; Ducray, R., WO 2009/ A1, 2009 Barlaam, B. C.; Ducray, R.; Kettle, J. G., US 7,718,653 B2, 2010
11 A graph of the log IC 50 values for tip-based serial dilution and dispensing versus acoustic dispensing with direct dilution shows a poor correlation between techniques (R 2 = 0.246) log IC 50-tips log IC 50-acoustic -3 acoustic technique always gave a more potent IC 50 value
12 Experimental Process Results Acoustic Model Acoustic Model Acoustic Model 14 Structures with Data Generate pharmacophore models for EphB4 receptor Test models against new data Test models against X-ray crystal structure pharmacophores Tip-based Model Tip-based Model Tip-based Model Results Initial data set of 14 WO2009/010794, US 7,718,653 Independent data set of 12 WO2008/ Independent crystallography data Bioorg Med Chem Lett 18:2776; 12 18:5717; 20:6242; 21:2207
13 Tyrosine kinase EphB4 Pharmacophores Generated with Discovery Studio (Accelrys) Cyan = hydrophobic Green = hydrogen bond acceptor Purple = hydrogen bond donor Acoustic Tip based Each model shows most potent molecule mapping Hydrophobic Hydrogen Hydrogen Observed vs. features (HPF) bond acceptor bond donor predicted IC 50 (HBA) (HBD) r Acoustic mediated process Tip-based process Ekins et al., PLOSONE, In press
14 Test set evaluation of pharmacophores An additional 12 compounds from AstraZeneca Barlaam, B. C.; Ducray, R., WO 2008/ A1, of these compounds had data for tip based dispensing and 2 for acoustic dispensing Calculated LogP and logd showed low but statistically significant correlations with tip based dispensing (r 2 = 0.39 p < 0.05 and 0.24 p < 0.05, N = 36) Used as a test set for pharmacophores The two compounds analyzed with acoustic liquid handling were predicted in the top 3 using the acoustic pharmacophore The Tip-based pharmacophore failed to rank the retrieved compounds correctly
15 Automated receptor-ligand pharmacophore generation method Pharmacophores for the tyrosine kinase EphB4 generated from crystal structures in the protein data bank PDB using Discovery Studio version Cyan = hydrophobic Green = hydrogen bond acceptor Purple = hydrogen bond donor Grey = excluded volumes Each model shows most potent molecule mapping Bioorg Med Chem Lett 2010, 20, Bioorg Med Chem Lett 2008, 18, Bioorg Med Chem Lett 2008, 18, Bioorg Med Chem Lett 2011, 21,
16 Summary In the absence of structural data, pharmacophores and other computational and statistical models are used to guide medicinal chemistry in early drug discovery. Our findings suggest acoustic dispensing methods could improve HTS results and avoid the development of misleading computational models and statistical relationships. Automated pharmacophores are closer to pharmacophore generated with acoustic data all have hydrophobic features missing from Tipbased pharmacophore model Importance of hydrophobicity seen with logp correlation and crystal structure interactions Public databases should annotate this meta-data alongside biological data points, to create larger datasets for comparing different computational methods.
17 Serial dilution IC 50 μm Log IC 50 tips Serial dilution IC 50 μm -40 Acoustic % Inhibition Acoustic vs. Tip-based Transfers Adapted from Spicer et al., Presentation at Drug Discovery Technology, Boston, MA, August Acoustic IC 50 μm Adapted from Wingfield. Presentation at ELRIG2012, Manchester, UK NOTE DIFFERENT ORIENTATION Aqueous % Inhibition Adapted from Wingfield et al., Amer. Drug Disco. 2007, 3(3): Data in this presentation Acoustic IC 50 μm Log IC 50 acoustic No Previous Analysis of molecule properties
18 Ekins et al., PLOSONE, In press Strengths and Weaknesses Small dataset size focused on one compound series No previous publication describing how data quality can be impacted by dispensing and how this in turn affects computational models and downstream decision making. No comparison of pharmacophores generated from acoustic dispensing and tip-based dispensing. No previous comparison of pharmacophores generated from in vitro data with pharmacophores automatically generated from X-ray crystal conformations of inhibitors. Severely limited by number of structures in public domain with data in both systems Reluctance of many to accept that this could be an issue
19 The stuff of nightmares? How much of the data in databases is generated by tip based serial dilution methods How much is erroneous Do we have to start again? How does it affect all subsequent science data mining etc Does it impact Pharmas productivity?
20 Simple Rules for licensing open data Could data open accessibility equal Disruption As we see a future of increased database integration the licensing of the data may be a hurdle that hampers progress and usability. 1: NIH and other international scientific funding bodies should mandate open accessibility for all data generated by publicly funded research immediately Williams, Wilbanks and Ekins. PLoS Comput Biol 8(9): e , 2012 Ekins, Waller, Bradley, Clark and Williams. DDT, 18:265-71, 2013
21 You can find CDD Booth 205 PAPER ID: PAPER TITLE: Dispensing processes profoundly impact biological assays and computational and statistical analyses April 8 th 8.35am Room 349 PAPER ID: PAPER TITLE: Enhancing High Throughput Screening For Mycobacterium tuberculosis Drug Discovery Using Bayesian Models April 9 th 1.30pm Room 353 PAPER ID: PAPER TITLE: Navigating between patents, papers, abstracts and databases using public sources and tools April 9 th 3.50pm Room 350 PAPER ID: PAPER TITLE: TB Mobile: Appifying Data on Anti-tuberculosis Molecule Targets April 10 th 8.30am Room 357 PAPER ID: PAPER TITLE: Challenges and recommendations for obtaining chemical structures of industry-provided repurposing candidates April 10 th 10.20am Room 350 PAPER ID: PAPER TITLE: Dual-event machine learning models to accelerate drug discovery April 10 th 3.05 pm Room 350
Data Quality Issues That Can Impact Drug Discovery
Data Quality Issues That Can Impact Drug Discovery Sean Ekins 1, Joe Olechno 2 Antony J. Williams 3 1 Collaborations in Chemistry, Fuquay Varina, NC. 2 Labcyte Inc, Sunnyvale, CA. 3 Royal Society of Chemistry,
More informationNavigating between patents, papers, abstracts and databases using public sources and tools
Navigating between patents, papers, abstracts and databases using public sources and tools Christopher Southan 1 and Sean Ekins 2 TW2Informatics, Göteborg, Sweden, Collaborative Drug Discovery, North Carolina,
More informationRetrieving hits through in silico screening and expert assessment M. N. Drwal a,b and R. Griffith a
Retrieving hits through in silico screening and expert assessment M.. Drwal a,b and R. Griffith a a: School of Medical Sciences/Pharmacology, USW, Sydney, Australia b: Charité Berlin, Germany Abstract:
More informationIntroduction to Chemoinformatics and Drug Discovery
Introduction to Chemoinformatics and Drug Discovery Irene Kouskoumvekaki Associate Professor February 15 th, 2013 The Chemical Space There are atoms and space. Everything else is opinion. Democritus (ca.
More informationReceptor Based Drug Design (1)
Induced Fit Model For more than 100 years, the behaviour of enzymes had been explained by the "lock-and-key" mechanism developed by pioneering German chemist Emil Fischer. Fischer thought that the chemicals
More informationStructural biology and drug design: An overview
Structural biology and drug design: An overview livier Taboureau Assitant professor Chemoinformatics group-cbs-dtu otab@cbs.dtu.dk Drug discovery Drug and drug design A drug is a key molecule involved
More informationDevelopment of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining
Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining Samer Haidar 1, Zouhair Bouaziz 2, Christelle Marminon 2, Tiomo Laitinen 3, Anti Poso
More informationAdvanced Medicinal Chemistry SLIDES B
Advanced Medicinal Chemistry Filippo Minutolo CFU 3 (21 hours) SLIDES B Drug likeness - ADME two contradictory physico-chemical parameters to balance: 1) aqueous solubility 2) lipid membrane permeability
More informationUsing AutoDock for Virtual Screening
Using AutoDock for Virtual Screening CUHK Croucher ASI Workshop 2011 Stefano Forli, PhD Prof. Arthur J. Olson, Ph.D Molecular Graphics Lab Screening and Virtual Screening The ultimate tool for identifying
More informationIntroduction. OntoChem
Introduction ntochem Providing drug discovery knowledge & small molecules... Supporting the task of medicinal chemistry Allows selecting best possible small molecule starting point From target to leads
More informationBioengineering & Bioinformatics Summer Institute, Dept. Computational Biology, University of Pittsburgh, PGH, PA
Pharmacophore Model Development for the Identification of Novel Acetylcholinesterase Inhibitors Edwin Kamau Dept Chem & Biochem Kennesa State Uni ersit Kennesa GA 30144 Dept. Chem. & Biochem. Kennesaw
More informationData Mining in the Chemical Industry. Overview of presentation
Data Mining in the Chemical Industry Glenn J. Myatt, Ph.D. Partner, Myatt & Johnson, Inc. glenn.myatt@gmail.com verview of presentation verview of the chemical industry Example of the pharmaceutical industry
More informationDr. Sander B. Nabuurs. Computational Drug Discovery group Center for Molecular and Biomolecular Informatics Radboud University Medical Centre
Dr. Sander B. Nabuurs Computational Drug Discovery group Center for Molecular and Biomolecular Informatics Radboud University Medical Centre The road to new drugs. How to find new hits? High Throughput
More informationComputational chemical biology to address non-traditional drug targets. John Karanicolas
Computational chemical biology to address non-traditional drug targets John Karanicolas Our computational toolbox Structure-based approaches Ligand-based approaches Detailed MD simulations 2D fingerprints
More informationIn Silico Investigation of Off-Target Effects
PHARMA & LIFE SCIENCES WHITEPAPER In Silico Investigation of Off-Target Effects STREAMLINING IN SILICO PROFILING In silico techniques require exhaustive data and sophisticated, well-structured informatics
More informationDifferent conformations of the drugs within the virtual library of FDA approved drugs will be generated.
Chapter 3 Molecular Modeling 3.1. Introduction In this study pharmacophore models will be created to screen a virtual library of FDA approved drugs for compounds that may inhibit MA-A and MA-B. The virtual
More informationUsing Bayesian Statistics to Predict Water Affinity and Behavior in Protein Binding Sites. J. Andrew Surface
Using Bayesian Statistics to Predict Water Affinity and Behavior in Protein Binding Sites Introduction J. Andrew Surface Hampden-Sydney College / Virginia Commonwealth University In the past several decades
More informationQSAR Modeling of ErbB1 Inhibitors Using Genetic Algorithm-Based Regression
APPLICATION NOTE QSAR Modeling of ErbB1 Inhibitors Using Genetic Algorithm-Based Regression GAINING EFFICIENCY IN QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS ErbB1 kinase is the cell-surface receptor
More informationHIGH-THROUGHPUT DETERMINATION OF AQUEOUS SOLUBILITY, PRECIPITATION OR COLLOIDAL AGGREGATE FORMATION IN SMALL MOLECULE SCREENING SETS
HIGH-THROUGHPUT DETERMINATION OF AQUEOUS SOLUBILITY, PRECIPITATION OR COLLOIDAL AGGREGATE FORMATION IN SMALL MOLECULE SCREENING SETS Introduction: Determining the aqueous solubility of a compound is an
More informationFRAGMENT SCREENING IN LEAD DISCOVERY BY WEAK AFFINITY CHROMATOGRAPHY (WAC )
FRAGMENT SCREENING IN LEAD DISCOVERY BY WEAK AFFINITY CHROMATOGRAPHY (WAC ) SARomics Biostructures AB & Red Glead Discovery AB Medicon Village, Lund, Sweden Fragment-based lead discovery The basic idea:
More informationChemBioNet: Chemical Biology supported by Networks of Chemists and Biologists. Affinity Proteomics Meeting Alpbach. Michael Lisurek 15.3.
ChemBioet: Chemical Biology supported by etworks of Chemists and Biologists Affinity Proteomics Meeting Alpbach Michael Lisurek 15.3.2007 - Introduction - Equipment Screening Unit - Screening Compound
More informationChemogenomic: Approaches to Rational Drug Design. Jonas Skjødt Møller
Chemogenomic: Approaches to Rational Drug Design Jonas Skjødt Møller Chemogenomic Chemistry Biology Chemical biology Medical chemistry Chemical genetics Chemoinformatics Bioinformatics Chemoproteomics
More informationTargeting protein-protein interactions: A hot topic in drug discovery
Michal Kamenicky; Maria Bräuer; Katrin Volk; Kamil Ödner; Christian Klein; Norbert Müller Targeting protein-protein interactions: A hot topic in drug discovery 104 Biomedizin Innovativ patientinnenfokussierte,
More informationGyörgy M. Keserű H2020 FRAGNET Network Hungarian Academy of Sciences
Fragment based lead discovery - introduction György M. Keserű H2020 FRAGET etwork Hungarian Academy of Sciences www.fragnet.eu Hit discovery from screening Druglike library Fragment library Large molecules
More informationDrug Design 2. Oliver Kohlbacher. Winter 2009/ QSAR Part 4: Selected Chapters
Drug Design 2 Oliver Kohlbacher Winter 2009/2010 11. QSAR Part 4: Selected Chapters Abt. Simulation biologischer Systeme WSI/ZBIT, Eberhard-Karls-Universität Tübingen Overview GRIND GRid-INDependent Descriptors
More informationCSD. CSD-Enterprise. Access the CSD and ALL CCDC application software
CSD CSD-Enterprise Access the CSD and ALL CCDC application software CSD-Enterprise brings it all: access to the Cambridge Structural Database (CSD), the world s comprehensive and up-to-date database of
More informationIn silico pharmacology for drug discovery
In silico pharmacology for drug discovery In silico drug design In silico methods can contribute to drug targets identification through application of bionformatics tools. Currently, the application of
More informationKinome-wide Activity Models from Diverse High-Quality Datasets
Kinome-wide Activity Models from Diverse High-Quality Datasets Stephan C. Schürer*,1 and Steven M. Muskal 2 1 Department of Molecular and Cellular Pharmacology, Miller School of Medicine and Center for
More informationRelative Drug Likelihood: Going beyond Drug-Likeness
Relative Drug Likelihood: Going beyond Drug-Likeness ACS Fall National Meeting, August 23rd 2012 Matthew Segall, Iskander Yusof Optibrium, StarDrop, Auto-Modeller and Glowing Molecule are trademarks of
More informationCheminformatics Role in Pharmaceutical Industry. Randal Chen Ph.D. Abbott Laboratories Aug. 23, 2004 ACS
Cheminformatics Role in Pharmaceutical Industry Randal Chen Ph.D. Abbott Laboratories Aug. 23, 2004 ACS Agenda The big picture for pharmaceutical industry Current technological/scientific issues Types
More informationFragment Hotspot Maps: A CSD-derived Method for Hotspot identification
Fragment Hotspot Maps: A CSD-derived Method for Hotspot identification Chris Radoux www.ccdc.cam.ac.uk radoux@ccdc.cam.ac.uk 1 Introduction Hotspots Strongly attractive to organic molecules Organic molecules
More informationPlan. Lecture: What is Chemoinformatics and Drug Design? Description of Support Vector Machine (SVM) and its used in Chemoinformatics.
Plan Lecture: What is Chemoinformatics and Drug Design? Description of Support Vector Machine (SVM) and its used in Chemoinformatics. Exercise: Example and exercise with herg potassium channel: Use of
More informationMedicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design
Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design Bela Torok Department of Chemistry University of Massachusetts Boston Boston, MA 1 Computer Aided Drug Design - Introduction Development
More informationVirtual screening in drug discovery
Virtual screening in drug discovery Pavel Polishchuk Institute of Molecular and Translational Medicine Palacky University pavlo.polishchuk@upol.cz Drug development workflow Vistoli G., et al., Drug Discovery
More informationCHAPTER 3. Pharmacophore modelling studies:
CHAPTER 3 Pharmacophore modelling studies: 3.1 Introduction: According to Langer & Wolber (2004), the key goal of computer-aided molecular design methods in medicinal chemistry is to reduce the time and
More informationSupporting Information
In Silico Identification of a ovel Hinge-Binding Scaffold for Kinase Inhibitor Discovery Yanli Wang a#, Yuze Sun b,a#, Ran Cao a#, Dan Liu a, Yuting Xie a, Li Li a, Xiangbing Qi a*, and iu Huang a* a.
More informationPrinciples of Drug Design
(16:663:502) Instructors: Longqin Hu and John Kerrigan Direct questions and enquiries to the Course Coordinator: Longqin Hu For more current information, please check WebCT at https://webct.rutgers.edu
More informationJoana Pereira Lamzin Group EMBL Hamburg, Germany. Small molecules How to identify and build them (with ARP/wARP)
Joana Pereira Lamzin Group EMBL Hamburg, Germany Small molecules How to identify and build them (with ARP/wARP) The task at hand To find ligand density and build it! Fitting a ligand We have: electron
More informationStructure based drug design and LIE models for GPCRs
Structure based drug design and LIE models for GPCRs Peter Kolb kolb@docking.org Shoichet Lab ACS 237 th National Meeting, March 24, 2009 p.1/26 [Acknowledgements] Brian Shoichet John Irwin Mike Keiser
More informationUser Guide for LeDock
User Guide for LeDock Hongtao Zhao, PhD Email: htzhao@lephar.com Website: www.lephar.com Copyright 2017 Hongtao Zhao. All rights reserved. Introduction LeDock is flexible small-molecule docking software,
More informationStructure-Activity Modeling - QSAR. Uwe Koch
Structure-Activity Modeling - QSAR Uwe Koch QSAR Assumption: QSAR attempts to quantify the relationship between activity and molecular strcucture by correlating descriptors with properties Biological activity
More informationIdentifying Interaction Hot Spots with SuperStar
Identifying Interaction Hot Spots with SuperStar Version 1.0 November 2017 Table of Contents Identifying Interaction Hot Spots with SuperStar... 2 Case Study... 3 Introduction... 3 Generate SuperStar Maps
More informationMedicinal Chemistry and Chemical Biology
Medicinal Chemistry and Chemical Biology Activities Drug Discovery Imaging Chemical Biology Computational Chemistry Natural Product Synthesis Current Staff Mike Waring Professor of Medicinal Chemistry
More informationPlan. Day 2: Exercise on MHC molecules.
Plan Day 1: What is Chemoinformatics and Drug Design? Methods and Algorithms used in Chemoinformatics including SVM. Cross validation and sequence encoding Example and exercise with herg potassium channel:
More informationVirtual Libraries and Virtual Screening in Drug Discovery Processes using KNIME
Virtual Libraries and Virtual Screening in Drug Discovery Processes using KNIME Iván Solt Solutions for Cheminformatics Drug Discovery Strategies for known targets High-Throughput Screening (HTS) Cells
More informationHydrogen Bonding & Molecular Design Peter
Hydrogen Bonding & Molecular Design Peter Kenny(pwk.pub.2008@gmail.com) Hydrogen Bonding in Drug Discovery & Development Interactions between drug and water molecules (Solubility, distribution, permeability,
More informationDesign and Synthesis of the Comprehensive Fragment Library
YOUR INNOVATIVE CHEMISTRY PARTNER IN DRUG DISCOVERY Design and Synthesis of the Comprehensive Fragment Library A 3D Enabled Library for Medicinal Chemistry Discovery Warren S Wade 1, Kuei-Lin Chang 1,
More informationCreating a Pharmacophore Query from a Reference Molecule & Scaffold Hopping in CSD-CrossMiner
Table of Contents Creating a Pharmacophore Query from a Reference Molecule & Scaffold Hopping in CSD-CrossMiner Introduction... 2 CSD-CrossMiner Terminology... 2 Overview of CSD-CrossMiner... 3 Features
More informationSupporting Information
Discovery of kinase inhibitors by high-throughput docking and scoring based on a transferable linear interaction energy model Supporting Information Peter Kolb, Danzhi Huang, Fabian Dey and Amedeo Caflisch
More informationUnlocking the potential of your drug discovery programme
Unlocking the potential of your drug discovery programme Innovative screening The leading fragment screening platform with MicroScale Thermophoresis at its core Domainex expertise High quality results
More informationPerforming a Pharmacophore Search using CSD-CrossMiner
Table of Contents Introduction... 2 CSD-CrossMiner Terminology... 2 Overview of CSD-CrossMiner... 3 Searching with a Pharmacophore... 4 Performing a Pharmacophore Search using CSD-CrossMiner Version 2.0
More informationDrug Informatics for Chemical Genomics...
Drug Informatics for Chemical Genomics... An Overview First Annual ChemGen IGERT Retreat Sept 2005 Drug Informatics for Chemical Genomics... p. Topics ChemGen Informatics The ChemMine Project Library Comparison
More informationBiologically Relevant Molecular Comparisons. Mark Mackey
Biologically Relevant Molecular Comparisons Mark Mackey Agenda > Cresset Technology > Cresset Products > FieldStere > FieldScreen > FieldAlign > FieldTemplater > Cresset and Knime About Cresset > Specialist
More information5.1. Hardwares, Softwares and Web server used in Molecular modeling
5. EXPERIMENTAL The tools, techniques and procedures/methods used for carrying out research work reported in this thesis have been described as follows: 5.1. Hardwares, Softwares and Web server used in
More informationGC and CELPP: Workflows and Insights
GC and CELPP: Workflows and Insights Xianjin Xu, Zhiwei Ma, Rui Duan, Xiaoqin Zou Dalton Cardiovascular Research Center, Department of Physics and Astronomy, Department of Biochemistry, & Informatics Institute
More informationCurrent Literature. Development of Highly Potent and Selective Steroidal Inhibitors and Degraders of CDK8
Current Literature Development of ighly Potent and Selective Steroidal Inhibitors and Degraders of CDK8 ACS Med. Chem. Lett. 2018, ASAP Rational Drug Development simplification Cortistatin A 16-30 steps;
More informationNanoliter Scale High-Throughput Protein Crystallography Screening with the Echo Liquid Handler
TM Application Note P100 Echo Liquid Handler Nanoliter Scale High-Throughput Protein Crystallography Screening with the Echo Liquid Handler Bonnie Edwards, David Harris Labcyte Inc. Abstract The Echo liquid
More informationEarly Stages of Drug Discovery in the Pharmaceutical Industry
Early Stages of Drug Discovery in the Pharmaceutical Industry Daniel Seeliger / Jan Kriegl, Discovery Research, Boehringer Ingelheim September 29, 2016 Historical Drug Discovery From Accidential Discovery
More informationTranslating Methods from Pharma to Flavours & Fragrances
Translating Methods from Pharma to Flavours & Fragrances CINF 27: ACS National Meeting, New Orleans, LA - 18 th March 2018 Peter Hunt, Edmund Champness, Nicholas Foster, Tamsin Mansley & Matthew Segall
More informationBUDE. A General Purpose Molecular Docking Program Using OpenCL. Richard B Sessions
BUDE A General Purpose Molecular Docking Program Using OpenCL Richard B Sessions 1 The molecular docking problem receptor ligand Proteins typically O(1000) atoms Ligands typically O(100) atoms predicted
More informationDOCKING TUTORIAL. A. The docking Workflow
2 nd Strasbourg Summer School on Chemoinformatics VVF Obernai, France, 20-24 June 2010 E. Kellenberger DOCKING TUTORIAL A. The docking Workflow 1. Ligand preparation It consists in the standardization
More informationLigandScout. Automated Structure-Based Pharmacophore Model Generation. Gerhard Wolber* and Thierry Langer
LigandScout Automated Structure-Based Pharmacophore Model Generation Gerhard Wolber* and Thierry Langer * E-Mail: wolber@inteligand.com Pharmacophores from LigandScout Pharmacophores & the Protein Data
More informationBridging the Dimensions:
Bridging the Dimensions: Seamless Integration of 3D Structure-based Design and 2D Structure-activity Relationships to Guide Medicinal Chemistry ACS Spring National Meeting. COMP, March 13 th 2016 Marcus
More informationSCULPT 3.0. Using SCULPT to Gain Competitive Insights. Brings 3D Visualization to the Lab Bench SPECIAL REPORT. 4 Molecular Connection Fall 1999
SPECIAL REPORT SCULPT 3.0 Brings 3D Visualization to the Lab Bench ith the acquisition of Interactive Simulations, Inc., last April, MDL added to its arsenal of discovery informatics tools a powerful analysis
More informationQSAR of Microtubule Stabilizing Dictyostatins
QSAR of Microtubule Stabilizing Dictyostatins Kia Montgomery BBSI 2007- University of Pittsburgh Department of Chemistry, Grambling State University Billy Day, Ph.D. Department of Pharmaceutical Sciences,
More informationDocking. GBCB 5874: Problem Solving in GBCB
Docking Benzamidine Docking to Trypsin Relationship to Drug Design Ligand-based design QSAR Pharmacophore modeling Can be done without 3-D structure of protein Receptor/Structure-based design Molecular
More informationAnalysis of a Large Structure/Biological Activity. Data Set Using Recursive Partitioning and. Simulated Annealing
Analysis of a Large Structure/Biological Activity Data Set Using Recursive Partitioning and Simulated Annealing Student: Ke Zhang MBMA Committee: Dr. Charles E. Smith (Chair) Dr. Jacqueline M. Hughes-Oliver
More informationMachine learning for ligand-based virtual screening and chemogenomics!
Machine learning for ligand-based virtual screening and chemogenomics! Jean-Philippe Vert Institut Curie - INSERM U900 - Mines ParisTech In silico discovery of molecular probes and drug-like compounds:
More informationNavigation in Chemical Space Towards Biological Activity. Peter Ertl Novartis Institutes for BioMedical Research Basel, Switzerland
Navigation in Chemical Space Towards Biological Activity Peter Ertl Novartis Institutes for BioMedical Research Basel, Switzerland Data Explosion in Chemistry CAS 65 million molecules CCDC 600 000 structures
More informationProtein-Ligand Docking Evaluations
Introduction Protein-Ligand Docking Evaluations Protein-ligand docking: Given a protein and a ligand, determine the pose(s) and conformation(s) minimizing the total energy of the protein-ligand complex
More informationChemoinformatics and information management. Peter Willett, University of Sheffield, UK
Chemoinformatics and information management Peter Willett, University of Sheffield, UK verview What is chemoinformatics and why is it necessary Managing structural information Typical facilities in chemoinformatics
More informationNext Generation Computational Chemistry Tools to Predict Toxicity of CWAs
Next Generation Computational Chemistry Tools to Predict Toxicity of CWAs William (Bill) Welsh welshwj@umdnj.edu Prospective Funding by DTRA/JSTO-CBD CBIS Conference 1 A State-wide, Regional and National
More informationDifferential Scanning Fluorimetry: Detection of ligands and conditions that promote protein stability and crystallization
Differential Scanning Fluorimetry: Detection of ligands and conditions that promote protein stability and crystallization Frank Niesen PX school 2008, Como, Italy Method introduction Topics Applications
More informationSupplementary Methods
Supplementary Methods MMPBSA Free energy calculation Molecular Mechanics/Poisson Boltzmann Surface Area (MM/PBSA) has been widely used to calculate binding free energy for protein-ligand systems (1-7).
More informationCSD. Unlock value from crystal structure information in the CSD
CSD CSD-System Unlock value from crystal structure information in the CSD The Cambridge Structural Database (CSD) is the world s most comprehensive and up-todate knowledge base of crystal structure data,
More informationQuantum Mechanical Models of P450 Metabolism to Guide Optimization of Metabolic Stability
Quantum Mechanical Models of P450 Metabolism to Guide Optimization of Metabolic Stability Optibrium Webinar 2015, June 17 2015 Jonathan Tyzack, Matthew Segall, Peter Hunt Optibrium, StarDrop, Auto-Modeller
More informationReaxys Medicinal Chemistry Fact Sheet
R&D SOLUTIONS FOR PHARMA & LIFE SCIENCES Reaxys Medicinal Chemistry Fact Sheet Essential data for lead identification and optimization Reaxys Medicinal Chemistry empowers early discovery in drug development
More informationExploring the chemical space of screening results
Exploring the chemical space of screening results Edmund Champness, Matthew Segall, Chris Leeding, James Chisholm, Iskander Yusof, Nick Foster, Hector Martinez ACS Spring 2013, 7 th April 2013 Optibrium,
More informationMedicinal Chemist s Relationship with Additivity: Are we Taking the Fundamentals for Granted?
Medicinal Chemist s Relationship with Additivity: Are we Taking the Fundamentals for Granted? J. Guy Breitenbucher Streamlining Drug Discovery Conference San Francisco, CA ct. 25, 2018 Additivity as the
More informationPreparing a PDB File
Figure 1: Schematic view of the ligand-binding domain from the vitamin D receptor (PDB file 1IE9). The crystallographic waters are shown as small spheres and the bound ligand is shown as a CPK model. HO
More informationLife Science Webinar Series
Life Science Webinar Series Elegant protein- protein docking in Discovery Studio Francisco Hernandez-Guzman, Ph.D. November 20, 2007 Sr. Solutions Scientist fhernandez@accelrys.com Agenda In silico protein-protein
More informationImplementation of novel tools to facilitate fragment-based drug discovery by NMR:
Implementation of novel tools to facilitate fragment-based drug discovery by NMR: Automated analysis of large sets of ligand-observed NMR binding data and 19 F methods Andreas Lingel Global Discovery Chemistry
More informationPriority Setting of Endocrine Disruptors Using QSARs
Priority Setting of Endocrine Disruptors Using QSARs Weida Tong Manager of Computational Science Group, Logicon ROW Sciences, FDA s National Center for Toxicological Research (NCTR), U.S.A. Thanks for
More informationViewing and Analyzing Proteins, Ligands and their Complexes 2
2 Viewing and Analyzing Proteins, Ligands and their Complexes 2 Overview Viewing the accessible surface Analyzing the properties of proteins containing thousands of atoms is best accomplished by representing
More informationJCICS Major Research Areas
JCICS Major Research Areas Chemical Information Text Searching Structure and Substructure Searching Databases Patents George W.A. Milne C571 Lecture Fall 2002 1 JCICS Major Research Areas Chemical Computation
More informationStructure-based maximal affinity model predicts small-molecule druggability
Structure-based maximal affinity model predicts small-molecule druggability Alan Cheng alan.cheng@amgen.com IMA Workshop (Jan 17, 2008) Druggability prediction Introduction Affinity model Some results
More informationCHEM 4170 Problem Set #1
CHEM 4170 Problem Set #1 0. Work problems 1-7 at the end of Chapter ne and problems 1, 3, 4, 5, 8, 10, 12, 17, 18, 19, 22, 24, and 25 at the end of Chapter Two and problem 1 at the end of Chapter Three
More informationSupplementary information
Electronic Supplementary Material (ESI) for MedChemComm. This journal is The Royal Society of Chemistry 2017 Supplementary information Identification of steroid-like natural products as potent antiplasmodial
More informationThe Case for Use Cases
The Case for Use Cases The integration of internal and external chemical information is a vital and complex activity for the pharmaceutical industry. David Walsh, Grail Entropix Ltd Costs of Integrating
More informationHigh Throughput In-Silico Screening Against Flexible Protein Receptors
John von Neumann Institute for Computing High Throughput In-Silico Screening Against Flexible Protein Receptors H. Sánchez, B. Fischer, H. Merlitz, W. Wenzel published in From Computational Biophysics
More informationLigand-receptor interactions
University of Silesia, Katowice, Poland 11 22 March 2013 Ligand-receptor interactions Dr. Pavel Polishchuk A.V. Bogatsky Physico-Chemical Institute of National Academy of Sciences of Ukraine Odessa, Ukraine
More informationZoe Blaxill Analytical Sciences Discovery Research. High Frequency Acoustic Technology: Evaluation for Compound Mixing and Dissolution in HTS.
Introduction Zoe Blaxill Analytical Sciences Discovery Research High Frequency Acoustic Technology: Evaluation for Compound Mixing and Dissolution in HTS. Introduction Current Issues Technology Overview
More informationMM-GBSA for Calculating Binding Affinity A rank-ordering study for the lead optimization of Fxa and COX-2 inhibitors
MM-GBSA for Calculating Binding Affinity A rank-ordering study for the lead optimization of Fxa and COX-2 inhibitors Thomas Steinbrecher Senior Application Scientist Typical Docking Workflow Databases
More informationKernel-based Machine Learning for Virtual Screening
Kernel-based Machine Learning for Virtual Screening Dipl.-Inf. Matthias Rupp Beilstein Endowed Chair for Chemoinformatics Johann Wolfgang Goethe-University Frankfurt am Main, Germany 2008-04-11, Helmholtz
More informationbcl::cheminfo Suite Enables Machine Learning-Based Drug Discovery Using GPUs Edward W. Lowe, Jr. Nils Woetzel May 17, 2012
bcl::cheminfo Suite Enables Machine Learning-Based Drug Discovery Using GPUs Edward W. Lowe, Jr. Nils Woetzel May 17, 2012 Outline Machine Learning Cheminformatics Framework QSPR logp QSAR mglur 5 CYP
More informationComputational Chemistry in Drug Design. Xavier Fradera Barcelona, 17/4/2007
Computational Chemistry in Drug Design Xavier Fradera Barcelona, 17/4/2007 verview Introduction and background Drug Design Cycle Computational methods Chemoinformatics Ligand Based Methods Structure Based
More informationPresentation Microcalorimetry for Life Science Research
Presentation Microcalorimetry for Life Science Research MicroCalorimetry The Universal Detector Heat is either generated or absorbed in every chemical process Capable of thermal measurements over a wide
More informationPIOTR GOLKIEWICZ LIFE SCIENCES SOLUTIONS CONSULTANT CENTRAL-EASTERN EUROPE
PIOTR GOLKIEWICZ LIFE SCIENCES SOLUTIONS CONSULTANT CENTRAL-EASTERN EUROPE 1 SERVING THE LIFE SCIENCES SPACE ADDRESSING KEY CHALLENGES ACROSS THE R&D VALUE CHAIN Characterize targets & analyze disease
More informationMechanistic insight into inhibition of two-component system signaling
Supporting Information Mechanistic insight into inhibition of two-component system signaling Samson Francis, a Kaelyn E. Wilke, a Douglas E. Brown a and Erin E. Carlson a,b* a Department of Chemistry,
More informationWelcome to Week 5. Chapter 9 - Binding, Structure, and Diversity. 9.1 Intermolecular Forces. Starting week five video. Introduction to Chapter 9
Welcome to Week 5 Starting week five video Please watch the online video (49 seconds). Chapter 9 - Binding, Structure, and Diversity Introduction to Chapter 9 Chapter 9 contains six subsections. Intermolecular
More information