fragment based drug discovery:automated analysis and reviewing · fragment based drug discovery:...

Fragment Based Drug Discovery: Automated Analysis and Reviewing Patrick Wheeler ACD/Labs, July 2014

Upload: others

Post on 22-Mar-2020

3 views

Category:

Documents

0 download

Report

Download

Embed Size (px):

TRANSCRIPT

Fragment Based Drug Discovery: Automated Analysis and Reviewing

Patrick Wheeler ACD/Labs, July 2014

NMR Screening

NMR is one of an array of screening possibilities in

the cascade of drug development steps.

http://www.pharmainfo.net/luckypharmacist/blog/fragment-based-drug-design-fbdd-alternative-approach-traditional-lead

Page 3: Fragment Based Drug Discovery:Automated Analysis and Reviewing · Fragment Based Drug Discovery: Automated Analysis and Reviewing Patrick Wheeler ACD/Labs, July 2014

NMR Screening

The Problem - Broadly

• An effort to understand ligand binding to biomolecules

• Many approaches are used

• Originally focused on small molecule fragments, designed to build up larger molecules

• Now includes general first-tier screening activity

Page 4: Fragment Based Drug Discovery:Automated Analysis and Reviewing · Fragment Based Drug Discovery: Automated Analysis and Reviewing Patrick Wheeler ACD/Labs, July 2014

NMR Screening

The Problem – Specific to NMR The ACD/Labs Solution

• Analysis by HQI*, Line position, Integral regions – Current: integral regions,

detect changes with and without competitor, find fragments that correlate

• Review by stack plots

• Rapid visualization and decision support

*Hit Quality Index

• Flood of data

• Data requires interpretation – Not all just numbers

• Visualization tools are poor

• Calculations are complex

Page 5: Fragment Based Drug Discovery:Automated Analysis and Reviewing · Fragment Based Drug Discovery: Automated Analysis and Reviewing Patrick Wheeler ACD/Labs, July 2014

Page 6: Fragment Based Drug Discovery:Automated Analysis and Reviewing · Fragment Based Drug Discovery: Automated Analysis and Reviewing Patrick Wheeler ACD/Labs, July 2014

Spectra Visualization

• Stack plot – Fragments on top

– Bound (protein) and Free (protein plus competitor) at bottom

• Tools to zoom in

Page 7: Fragment Based Drug Discovery:Automated Analysis and Reviewing · Fragment Based Drug Discovery: Automated Analysis and Reviewing Patrick Wheeler ACD/Labs, July 2014

Metadata

• Measurements of similarity

• Confidence value: Fraction of fragment lines decreased x Fraction of explained lines decreased

• Confidence can be determined to best meet customer needs

Page 8: Fragment Based Drug Discovery:Automated Analysis and Reviewing · Fragment Based Drug Discovery: Automated Analysis and Reviewing Patrick Wheeler ACD/Labs, July 2014

Workflow

• Analyze data – Data analysis fully customizable for customer’s data types and best

automation of hit detection

– Data types dealt with so far: Relaxation, Water LOGSY, STD

– Analysis tools: HQI, Line counts, Integral region count

• Open dataset – One batch at a time

– Can display all or subset of data

– Zoom, find regions that indicate binding, find fragments with lines in region

• Mark CSV with “hits”: can be imported into external systems

Page 9: Fragment Based Drug Discovery:Automated Analysis and Reviewing · Fragment Based Drug Discovery: Automated Analysis and Reviewing Patrick Wheeler ACD/Labs, July 2014

Analysis kickoff

Page 10: Fragment Based Drug Discovery:Automated Analysis and Reviewing · Fragment Based Drug Discovery: Automated Analysis and Reviewing Patrick Wheeler ACD/Labs, July 2014

Configurable

Page 11: Fragment Based Drug Discovery:Automated Analysis and Reviewing · Fragment Based Drug Discovery: Automated Analysis and Reviewing Patrick Wheeler ACD/Labs, July 2014

Analysis Running

Page 12: Fragment Based Drug Discovery:Automated Analysis and Reviewing · Fragment Based Drug Discovery: Automated Analysis and Reviewing Patrick Wheeler ACD/Labs, July 2014

Review data

Page 13: Fragment Based Drug Discovery:Automated Analysis and Reviewing · Fragment Based Drug Discovery: Automated Analysis and Reviewing Patrick Wheeler ACD/Labs, July 2014

Data Review

• Visually check changes between spectra with and without competitor

• Find Fragments with lines in same region

Page 14: Fragment Based Drug Discovery:Automated Analysis and Reviewing · Fragment Based Drug Discovery: Automated Analysis and Reviewing Patrick Wheeler ACD/Labs, July 2014

Metadata

• Provides – Ratings of similarity

– Automated hit analysis

– Regions of change

• Legend – Color coded

– Configurable

Page 15: Fragment Based Drug Discovery:Automated Analysis and Reviewing · Fragment Based Drug Discovery: Automated Analysis and Reviewing Patrick Wheeler ACD/Labs, July 2014

Mark hits

• Analyst can mark hits (or unmark hits that are selected by automated analysis)

• Selected hits are automatically entered into spreadsheet

Page 16: Fragment Based Drug Discovery:Automated Analysis and Reviewing · Fragment Based Drug Discovery: Automated Analysis and Reviewing Patrick Wheeler ACD/Labs, July 2014

CSV Output

Page 17: Fragment Based Drug Discovery:Automated Analysis and Reviewing · Fragment Based Drug Discovery: Automated Analysis and Reviewing Patrick Wheeler ACD/Labs, July 2014

Fragment Screening by NMR in Drug Discovery - Bruker · Fragment Screening by NMR in Drug Discovery Dr. Stefan Jehle, Bruker BioSpin Dr. Pavel Kessler, Bruker BioSpin German Users

TETHERING: Fragment-Based Drug Discovery

Native Mass Spectrometry in Fragment-Based Drug Discovery

Fragment-based Approaches in Drug Discoverydownload.e-bookshelf.de/download/0000/6029/87/L-G...Fragment-based Approaches in Drug Discovery Edited by Wolfgang Jahnke and Daniel A. Erlanson

FRAGMENT BASED DRUG DESIGN DOWN UNDER …...1 FRAGMENT BASED DRUG DESIGN DOWN UNDER 2019 Monash Institute of Pharmaceutical Sciences Monash Unviersity (Parkville Campus) 381 Royal

Sydney Analytical Fragment Based Drug Discovery › content › dam › corporate › ... · Fragment Based Drug Discovery Equipment and Expertise Surface Plasmon Resonance (SPR)

Fragment Based Drug Discovery with Surface Plasmon Resonance

Fragment-Based Drug Discovery Applied to Hsp90. Discovery of

Computational Fragment-based Discovery of Allosteric ...d-scholarship.pitt.edu/31577/1/Fragment_Allosteric_mGlu5_thesis_Bi… · Computational fragment-based drug discovery (FBDD)

Jeffrey Albert | FBDD 2014 | Fragment Assisted Drug Discovery

Introduction to Fragment-based Drug Discovery …catalogimages.wiley.com/images/db/pdf/9780470058138.excerpt.pdf · Introduction to Fragment-based Drug Discovery 3 a rapidly increasing

Fragment based drug discovery in teams of … · Fragment based drug discovery in teams of medicinal and computational chemists Carsten Detering ©

CzeekD: Fragment-based de novo Drug Design System for ......CzeekD: Fragment-based de novo Drug Design System for Drug Discovery Edmund Taylo Kyoto Constella Technologies Co., Ltd

Fragment Screening by NMR in Drug Discovery – F Methods · Fragment Screening by NMR in Drug Discovery – 19F Methods Dr. Stefan Jehle, Bruker BioSpin ... from efficient fragments

Fragment Based Drug Discovery:Automated …img.jp.fujitsu.com/.../acd/seminar/2014/Seminar2014-05.pdfFragment Based Drug Discovery: Automated Analysis and Reviewing Patrick Wheeler

Fragment based Drug Discovery; Design and Validation of a

From Receptors to Ligands: Fragment-assisted Drug Design for

TETHERING: Fragment- Based Drug Discovery...Fragment-Based Drug Discovery • Link many small molecules with weak binding to form a molecule with strong affinity. • Screen by positive

The Selcia Fragment Library: Design, Analysis & Quality ...Fragment Library, represents a unique and powerful tool for fragment-based drug discovery. The Selcia Fragment Library: Design,

3D-RISM‑DOCK: A New Fragment-Based Drug Design Protocol

Fragment-based drug discovery to identify small molecule ......the RAS/MAPK pathway using fragment -based drug design: ERK1/2 Fragment IC 50 76 μ M Lead IC 50 0.0030 μ M Heightman

Fragment-based drug discovery - DiVA portal

Fragment-Based Drug Design Strategies

Binding thermodynamics discriminates fragments from ...csmres.co.uk/...discriminates-fragments-from-druglike...fragment-based-drug-discovery.pdfbiophysical methods to fragment-based

A role for fragment-based drug design in developing novel ... · design strategies. Keywords: fragment-based drug design, CNS, dopamine, structure, target introduction The cost of

Reviewing Ligand-Based Rational Drug Design: The - MDPI.com

Computational fragment-based drug design to explore the ...Computational fragment-based drug design to explore the hydrophobic sub-pocket of the mitotic kinesin Eg5 allosteric binding

Applications of NMR in (Fragment‐Based) Drug Discovery · 2017-07-18 · Applications of NMR in (Fragment‐Based) Drug Discovery CCPN Conference 2017 University of Stirling 13thJuly

Mnova Software Tools for Fragment-Based Drug Discoveryresources.mestrelab.com/wp-content/uploads/2017/04/Webinar-Mnova... · Agenda Brief intro on fragment-based drug discovery (FBDD)

Fragment library screening and characterization with … · Fragment library screening and characterization with Biacore ... is a potentially important tool in fragment-based drug

ACFIS: a web server for fragment-based drug discovery

Fragment Fields in Drug Discovery - cresset-group.com · fields in the context of fragment based drug discovery. Introduction. Fields. Application of the XED force field provides

FRAGMENT- BASED DRUG DESIGN

Fragment Based Drug Discovery on Pioneer Systems using ... · Fragment-based drug design (FBDD) has become an increas-ingly popular platform for the identification of lead candidates

Fragment Based Drug Discovery