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Drug Discovery: Key Concepts in identifying drug leads

4/14/2014

How do you decide which leads to follow when developing new drugs? Join Dr. Tudor Oprea and Dr. Christopher Lipinski as they discuss the Rule of Five, how drug-likeness is a deceiving concept and how lessons from the past may guide the present. Tune in and ask your questions during Part 3 of our Drug Discovery Series.

Watch this live webinar from the American Chemical Society on Thursday, April 24, 2014 @ 2pm ET

This webinar is also available on the following dates:
Apr 24, 2014 2:00 PM - 3:00 PM EDT
May 29, 2014 2:00 PM - 3:00 PM EDT
Jun 26, 2014 2:00 PM - 3:00 PM EDT
Jul 31, 2014 2:00 PM - 3:00 PM EDT
Sep 25, 2014 2:00 PM - 3:00 PM EDT
Oct 30, 2014 2:00 PM - 3:00 PM EDT

Live ACS Webinars® are free to the public.

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Virtual Screening Workflow with the ZINC library on the apple cluster

3/6/2014

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SP
Make a directory and include the following files:

Example of SP.in file:
USECOMPMAE YES
NREPORT 30000
RINGCONFCUT 2.500000
GRIDFILE /home/eva/Zinc_screening/SP_1MV9/1MV9_no_wat_glide-grid.zip
LIGANDFILE /home/ZINC/druglike-Zinc-library-mol2/3_p0.0.mol2
LIGFORMAT mol2

Run the make_dirs script --> creates 88 folders (0-87)
Run the copy_files2 script --> leave the glide-dock_SP_0.in file out of its folder to run the script and when it is finished then cut+paste it to folder_0.
Use the submit_SP_all script to run the SP on apple cluster. In my case I used to put up to 12 jobs in each node ( modify this line of the script: for (( i = 76 ; i<=87; i++ )) ). Due to the fact that the jobs were put randomly to the nodes and in order to have up to 12 jobs on each node, I was using first some "fake" gromacs runs to use 12 cores and left the other 12 free for screening runs (Evi's idea! Thank's Evi!!).
When the run is finished you should check all the 88 directories and see if you have outputs like: e.g. glide-dock_SP_8_pv.maegz. If something goes wrong and the run has stopped then you will see e.g. glide-dock_SP_8_raw.maegz as an output. Then you should copy your glide-dock_SP_8.in to glide-dock_SP_8_b.in and run it from the ligand that it had stopped. Finally, you will have: glide-dock_SP_8_raw.maegz and glide-dock_SP_8_b_pv.maegz. Both are useful! Don't delete the first one!
In order to finish the SP process you have to take the top-scored 40.000 compounds from all the directories and put them to a new file (SP_top40000_1MV9_pv.maegz) to use as an input for the XP process.

You can run the GlideSortScript_ZINC.csh script to acheive this result. The content of the script is the following: (You have to add the possible raw.maegz files,too.)
/opt/schrodinger/utilities/glide_sort -n 40000 -o SP_top40000_1MV9_pv.maegz -r SP_top40000_1MV9.rept -hbond_cut 0.00 -cvdw_cut 0.00 -metal_cut 10.00 \ db3_p0.0/glide-dock_SP_0_pv.maegz \db3_p0.1/glide-dock_SP_1_pv.maegz \db3_p0.2/glide-dock_SP_2_pv.maegz \db3_p0.3/glide-dock_SP_3_raw.maegz \db3_p0.3/glide-dock_SP_3_b_pv.maegz \ etc.

XP
Each XP directory includes:

grid.zip file
SP_top40000_1MV9_pv.maegz (output of SP)
XP.in files (I split them into 8 files in my case)

Example of XP.in file:
WRITEREPT YES
WRITE_RES_INTERACTION YES
WRITE_XP_DESC YES
USECOMPMAE YES
POSTDOCK_NPOSE 10
LIGAND_END 10000
LIGAND_START 5001 (this line is not included in the XP_1.in file as it starts from the beginning)
MAXREF 800RINGCONFCUT 2.500000
GRIDFILE /home/eva/XP_Zinc/1MV9_XP_Zinc_2_8/1MV9_no_wat_glide-grid.zip
LIGANDFILE /home/eva/XP_Zinc/1MV9_XP_Zinc_2_8/SP_top40000_1MV9_pv.maegz
PRECISION XP

So, I split it to 8 XP directories:
0 - 5000, 5001 - 10000, 10001 - 15000, ..., 35001 - 40000

Run each one on the cluster or on our PCs manually :
/opt/schrodinger/glide 1MVC_Zinc_XP1.in -HOST xgrid-server
/opt/schrodinger/glide 1MVC_Zinc_XP2.in -HOST xgrid-server etc.

Finally you take the top-scored 1000 compounds (as we did before for the SP process where we took the 40.000 top-scored ) using the same script (GlideSortScript_ZINC.csh):

/opt/schrodinger2012/utilities/glide_sort -n 1000 -o file_XP_1000_pv.maegz -r file_XP_1000_.rept -hbond_cut 0.00 -cvdw_cut 0.00 -metal_cut 10.00 glide-dock_XP_0_pv.maegz glide-dock_XP_1_pv.maegz glide-dock_XP_2_pv.maegz glide-dock_XP_3_pv.maegz glide-dock_XP_4_pv.maegz glide-dock_XP_5_pv.maegz glide-dock_XP_6_pv.maegz glide-dock_XP_7_pv.maegz glide-dock_XP_8_pv.maegz

Some useful tips:

Run faster with the -LOCAL flag:
/opt/schrodinger/glide -LOCAL file.in

path for ZINC on apple:
/Network/Servers/xgrid-Server.xgrid/Volumes/RAID/NetUsers/pgkeka/PI3K/Screening/ZINC/druglike-Zinc-library-mol2/

Apple cluster run-command:
/opt/schrodinger/glide your_XP_file.in -HOST xgrid-server

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Drug Discovery from A to Z

2/20/2014

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What does it take to bring a drug on to the market? Learn the stages and challenges of every step by tuning in to the ACS Webinars Drug Discovery Series.
Register for the series which will be broadcast on the last Thursday of each month beginning February 2014 by clicking below.

https://www2.gotomeeting.com/register/251473674

Overview of the Drug Discovery and Development Process
Session 1: February 27, 2014
Dr. Derek Lowe (Vertex), Dr. Richard Connell (Pfizer) & Dr. Nicholas Meanwell (Bristol-Myers Squibb)

Primer in Drug Target Classes
Session 2: March 27, 2014
Dr. John P. Overington (European Bioinformatics Institute)

Key Concepts in Identifying Drug Leads
Session 3: April 24, 2014
Information on speakers coming soon.

Lead Optimization – Building Efficacy & Safety
Session 4: May 29, 2014
Information on speakers coming soon.

Fail Fast and Fail Early: Starting your Clinical Trials
Session 5: June 26, 2014
Information on speakers coming soon.

The Big Expense: Clinical Trials Phase 3
Session 6: July 31, 2014
Information on speakers coming soon.

Pharmacoeconomics and IP Strategies in Drug Development
Session 7: September 25, 2014
Information on speakers coming soon.

Future of Drug Discovery – Challenges, Risks and Rewards
Session 8: October 30, 2014
Information on speakers coming soon.
- See more at: http://acswebinars.org/drug-discovery#sthash.jpA7pE2H.dpuf

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In silico solubility predictions

3/12/2013

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Here is a review on solubility predictions, along with a list of the most popular softwares.
http://cadd.suda.edu.cn/Group/papers/review8.pdf

Zoe

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2012 Structure-Based Drug Design Conference presentations free online

2/26/2013

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You can download complimentary speaker presentations from the CHI's 2012 Structure-Based Drug Design (SBDD) conference by simply filling in a registration form here:

Making Docking/Scoring Calculations More Accurate via Error Analysis
Authored by: Kenneth M. Merz, Jr., Ph.D., Department of Chemistry, Quantum Theory Project, University of Florida

Challenges facing computational biology
Water models and water dimer
2010 GPCR docking and modeling competition
What about the docking funnel?

Download Presentation

Rational Approaches to Improving Selectivity in Drug Design
Authored by: Woody Sherman, Ph.D., Vice President, Applications Science, Shrodinger

Factors contributing to selectivity
Shape complementarity: Clash with decoy
- Remove decoy interactions
Induced fit of target
Experimental validation

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Structure based Ligand Discovery for GPCRs
Authored by: Ruben Abagyan, Ph.D., Professor, Skaggs School of Pharmacy & Pharmaceutical Sciences, San Diego Supercomputer Center, University of California, San Diego

Growing understanding of GPCR structure and function
Docking to flexible sites: methods and benchmarks
2010 GPCR docking and modeling competition
Ligand guided modeling of unsolved GPCRs and alternative states

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Making Decisions in Fragment-Based Drug Discovery
Authored by: Rod Hubbard, Ph.D., Director, Structural Sciences, Vernalis Ltd.

Overview of fragment-based methods
- Some (old) examples of successes
Some fragmentology
- Hit rates and target druggability
- Predicting fragment poses
- Selectivity
How to make decisions on which fragments to progress?
What are the opportunities for computational methods?

Download Presentation

This is the agenda for the 2013 Structure-Based Drug Design Conference.

Zoe

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Free online course on Drug Discovery, Development, and Commercialization

2/24/2013

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Coursera.org offers 323 free online courses from major universities on a variety of subjects such as: Financial Engineering and Risk Management, AIDS, Introductory Human Physiology, Synapses, Neurons and Brains and more!

The Drug Discovery, Development & Commercialization course is offered by UC San Diego (Drs Williams S. Ettouati and Joseph D. Ma). Students will learn the process of drug discovery and development through specific examples of case studies to better understand the issues facing the challenges of delivering a new drug on the market. At the completion of this course you will be able to have a better understanding of how a small or large molecule becomes a pharmaceutical drug.

The Next Session starts Apr 19th 2013 for a 9 weeks long course.

Here is the syllabus and signup form.

Zoe

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Databases for Chemical Structure Search

1/14/2013

25 Comments

Apart from the well-known SciFinder database, free databases for chemical structure search are the following:

1) Pubchem. PubChem, released in 2004, provides information on the biological activities of small molecules. PubChem is organized as three linked databases within the NCBI's Entrez information retrieval system. These are PubChem Substance, PubChem Compound, and PubChem BioAssay. PubChem also provides a fast chemical structure similarity search tool. More information about using each component database may be found using the links in the homepage.
Links from PubChem's chemical structure records to other Entrez databases provide information on biological properties.

2) ChemSpider. ChemSpider is a free chemical structure database providing fast text and structure search access to over 28 million structures from hundreds of data sources.

3) ChemFrog. ChemFrog is a chemical database that offers over 1 million commercially available chemicals and vendor information.

4) ChemDB. ChemDB is the IGB Chemical Database: The most diverse and useful set of chemoinformatics tools and applications available to the public. Applications: Chemical Search Find a chemical by basic criteria like molecular weight and predicted logP, or by the more abstract notion of structural similarity. Virtual Chemical Space Interactively deconstruct target compounds into component precursors and reconstruct similar building-blocks into combinatorial libraries representing the "virtual chemical space" near the target compound. Reaction Explorer Interactive system for learning and practicing reactions, syntheses and mechanisms in organic chemistry, with advanced support for the automatic generation of random problems, curved-arrow mechanism diagrams, and inquiry-based learning. COSMOS Predicts 3D small molecule structures from various standard 2D formats Reaction Predictor Predicts Mechanistic Reactions Using Machine Learning.

5) iScienceSearch. An Internet search engine for chemists. iScienceSearch also supports mobile devices and it works well to draw structures on something like an iPad. We use JSDraw from Scilligence (www.scilligence.com) to draw chemical structures. This is a good application to find out for yourself if mobile devices are useful for research. Please remember to allow pop-ups otherwise you don’t see the result page. Links to tools that predict biological activities and many other parameters of a structure, like logP are incorporated. PASS (Prediction of Activity Spectra of Substances) (www.akosgmbh.de/pass) predicts with high accuracy about 4000 effects for a compound.

6) Chemicalize (www.chemicalize.org ) from ChemAxon calculates structure parameters.

7) The DistilBio (a powerful, federated, life sciences search engine) new release now has instant display of results. http://distilbio.com With instantaneous search results and auto-complete, it is now even easier to find the research you are looking for all in one place. Visit the site and try it with "Aspirin".

Zoe

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ChEMBL resources for drug discovery

12/3/2012

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ChEMBLdb - a drug discovery SAR and bioactivity database.
SARfari - a sequence, binding site, structure, SAR integration platform.
DrugEBIlity - Drug target annotation & prioritisation.
ChEMBL-malaria and ChEMBL-NTD Data repository for neglected tropical diseases.
Open Source Intelligence (OSINT), Public-Private partnerships & Precompetitive activities.

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Drug Discovery: Key Concepts in identifying drug leads

Virtual Screening Workflow with the ZINC library on the apple cluster

Drug Discovery from A to Z

In silico solubility predictions

2012 Structure-Based Drug Design Conference presentations free online

Free online course on Drug Discovery, Development, and Commercialization

Databases for Chemical Structure Search

ChEMBL resources for drug discovery

Alexis, Michalis, Danai, Panos, Sotiris, Nastazia, Vassilis, Zoe

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