June 2017 newsletter

Flare release imminent: New insights for structure-based design

With the release of Flare imminent, Tim Cheeseright acknowledges the dedicated alpha and beta testers who have contributed to this exciting new application for structure-based design.

Molecular design towards Protein-Protein Interaction inhibitors

Martin Slater explores a powerful combination of cutting edge ligand and structure-based modeling using Flare and Blaze to see what could usefully be done with PPIs.

Using computational methods to elucidate protein-ligand interactions

Developing a robust binding hypothesis can lead to the discovery of new actives, broaden your optimization options, or help secure a back-up series. Cresset Discovery Services routinely uses homology modeling to move projects on to the next step.

Latest Spark reagent databases

The latest version of the Spark reagent databases is available now. Updated information on reagent availability from over 150 trusted suppliers can be downloaded using the Spark Database Updater. Contact us for other ways to keep up-to-date with Spark reagents.

Cresset applications licensed by Shiv Nadar University, India

Cresset supports teaching of computational chemistry though flexible software licenses and educational discounts. This month Shiv Nadar University, India, have licensed Forge and Spark to educate the computational chemists of the future.

We’re hiring!

Cresset applications licensed by Shiv Nadar University, India, to teach computational chemists of the future

Cambridge, UK – 20 June 2017 – Cresset, innovative provider of software and contract research services for small molecule discovery and design, announces that the Shiv Nadar University, India, has licensed the following applications to educate the computational chemist of the future: Forge – powerful ligand-focused workbench for SAR and design; and Spark – scaffold hopping application for progressing through lead optimization faster.

“Cresset actively supports academic research by providing flexible licensing terms,” says Dr David Bardsley, Commercial Director at Cresset. “We are delighted that Shiv Nadar University, India, joined the growing number of academics who are using our applications globally.”

“We pride ourselves on providing our students with the best tools for computational modeling and design,” says Professor N. Sukumar, Department of Chemistry, Shiv Nadar University. “By using Cresset technology through hands-on use of Forge and Spark, our students will be better prepared for a career in computational chemistry.”

Download press release.

Re-Pharm and Cresset Discovery Services to attend BIO International for partnering

Cambridge, UK – June 13, 2017 – Cresset, innovative provider of software and contract research services for small molecule discovery and design, and Re-Pharm, an early-stage drug discovery and development company that uses computational chemistry for re-profiling, will attend BIO International in San Diego on June 19-22.

“I am looking for partners to progress the anti-inflammatory compound RP0217 through early clinical development and clinical trials” says Dr Robert Scoffin, CEO of Re-Pharm. “RP0217 is a novel anti-inflammatory showing excellent standalone activity plus a strong steroid-sparing synergy with standard glucocorticoids. Re-Pharm holds patents on the use of RP0217 for the treatment or prevention of respiratory and gastrointestinal inflammatory disorders and for its use with and without co-formulated or co-administered steroids in topical ophthalmic indications, specifically conjunctivitis and uveitis, and prophylactic use in surgical applications such as LASIK.”

 “Cresset Discovery Services consultants bring a fresh perspective, years of industry experience, outstanding science and a complete professional service” says Dr David Bardsley, Commercial Director of Cresset Discovery Services. “Having delivered more than 200 early phase discovery projects to many leading pharmaceutical, biotech, agrochemical, flavor and fragrance companies, I look forward to discussing how we can advance company research projects.”

May 2017 newsletter

Last chance to register for The Cresset User Group Meeting

Register by 16th June to secure your place at our 15th Anniversary User Group Meeting.

  • June 29th, Scientific program
    • Official launch of Flare, our new structure-based design application
    • Update on science and ligand-based design applications
    • Customers share their experience of Cresset technology
    • Limited accommodation available at The Møller Centre
  • June 30th, Hands-on software workshops. Limited spaces remain for the following workshops:
    • Introduction to Flare for computational chemists
    • Introduction to Flare for medicinal and synthetic chemists
    • 3D-QSAR
    • Torch

Water stability is key to designing novel patentable chemistry

Read about how Cresset Discovery Services informed the design of novel ligands for a customer target, which led to patent.

Help with writing your grant application

See how we can help before you even start writing your grant application.

What can Torch do for you that TorchLite can’t?

We hope you enjoy using TorchLite, our freeware 3D molecule viewer, editor and design tool, but did you know how much more you can do with the full power of Torch?

Web clips

We’ve added to our GUI tips and tricks with the following tutorials, which use TorchLite, our free powerful 3D molecule viewing, editing and design application.

  • Structural changes and fields
  • Visualizing field changes to understand SAR

Electrostatics of heterocyclic rings and the Topliss tree

TorchLite has been used to illustrate 2D structures next to their 3D charge distribution patterns. Download the following illustrations:

  • Electrostatics of heterocyclic rings
  • Electrostatics of the Topliss Tree

Scientific program and workshops announced for The Cresset User Group Meeting, 29th – 30th June 2017, Cambridge, UK

Cambridge, UK – 10 May 2017 – Cresset, innovative provider of software and contract research services for small molecule discovery and design, announces full line-up for The Cresset User Group Meeting, 29th – 30th June 2017 in Cambridge, UK.

The scientific program on 29th June 2017 features speakers from 4 continents. Cresset scientists will present ‘New Insights for Structure-based Design with Flare’, ‘Peeking into the Heart of New Cresset Science’ and ‘What’s New in Ligand-based Design’. In addition, delegates will hear from:

  • AbbVie, USA: Important Aspects of Fragment Screening Collection Design
  • Bayer Pharma, Germany: In SilicoADMET at Bayer: Technologies and Applications
  • BioBlocks Inc., USA: The CFL: A 3D Enabled Fragment Library for Medicinal Chemistry Discovery
  • Cancer Therapeutics CRC, Australia: Integrating the Cresset Platform into Cancer Therapeutics CRC (CTx)
  • Evotec, UK: What Should I Make Next?
  • Institute for Stem Cell Biology and Regenerative Medicine, India: Representation of Small Molecule as Molecular Field Points Empowers Computational Chemists
  • International Flavors and Fragrances, USA: Can Cresset Tools Inform Fragrance Molecule Design?
  • Lilly, UK: Structure-blinded Virtual Screening: Use of Cresset Blaze in the Lilly Open Innovation Drug Discovery Program
  • University of Bristol, UK: Understanding Protein-ligand Binding at the Molecular Level: Using Swap-based Methods to Visualise Binding Free Energy Components
  • University of Bristol, UK: Virtual Reality and Real-time Molecular Dynamics for Chemistry
  • University of Edinburgh, UK: Molecular Simulation and Experimental Approaches to Ensemble-based Drug Design

Workshops on 30th June give computational, medicinal and synthetic chemists the opportunity to get hands-on with Cresset applications:

  • Flare, new insights for structure-based design
  • SAR with Forge using Activity Atlas models and Activity Miner
  • Spark, to quickly generate novel ideas and bioisosteres for molecule cores and R-groups
  • Virtual screening, using Blaze Cloud
  • 3D-QSAR, using Forge to improve compound design
  • Torch, for optimizing more than potency

“We have an exciting, diverse and varied program of speakers this year and I’m looking forward to hearing the latest on their research,” says Dr Robert Scoffin, CEO at Cresset. “The meeting will also mark the launch of Flare, our new workbench for structure-based design. Workshop places are almost fully booked for hands-on sessions with Flare and our other innovative applications for molecule design.”

Read abstracts, biographies, workshop schedule and register: http://www.cresset-group.com/cugm17/

April 2017 newsletter

Last chance for early access to Flare, new structure-based design application

Contact your account manager to join the final round of Flare testing and gain early access to this cutting edge structure-based design method with intuitive GUI.

The Cresset User Group Meeting

June 29th, Scientific program

  • Official launch of Flare, our new structure-based design application
  • Update on science and ligand-based design applications
  • Invited speakers from 4 continents share their use of Cresset applications on topics including fragment screening, library design, protein-ligand binding, virtual screening and fragrance molecule design.

June 30th, Hands-on software workshops

Due to demand which meant some workshops were fully booked, we have now created additional spaces. If the workshop you were interested in was fully booked then check back to see if space is now available.

Hit to lead

A long-standing customer had a hit series with good activity but poor properties. See how Cresset Discovery Services worked closely with the customer to formulate a plan of action to optimize the compound properties while maintaining potency.

Recent citations

See the following new citations:

  • Discovery of Compounds that Positively Modulate the High Affinity Choline Transporter
  • Chemical composition and phagocyte immunomodulatory activity of Ferula iliensis essential oils
  • Structure-Based Library Design and Fragment Screening for the Identification of Reversible Complement Factor D Protease Inhibitors
  • Field Based 3D-QSAR Model of KATP Channel Activation by 4, 6 Di-substituted Benzopyran Derivatives

Presentations from ACS

Download our presentation and posters from the 253rd ACS National Meeting. Also available are the presentation and poster by the University of Bristol which feature Flare, our new structure-based design application.

Presentations and posters from 253rd American Chemical Society National Meeting

Download our presentation and posters from the 253rd ACS National Meeting. Also available is the presentation, and poster, by the University of Bristol which features Flare, our new structure-based design application.

Improving new molecule design using electrostatics

MEDI poster 135

Tim Cheeseright, Director of Products, Cresset

Electrostatics are critical to ligand binding and yet largely overlooked in new molecule design due to the difficulty in calculation and visualization of meaningful potentials. We have previously shown how electrostatics can be used effectively for scaffold hopping, virtual screening, ligand alignment and SAR interpretation. In this poster we will focus on ligand and protein electrostatics. We will show how considering the changes in ligand electrostatics improves the outcome for new molecule design. Going beyond traditional H-bonding based pharmacophore descriptors enables designers to map the effect of molecular changes on the full electrostatic potential of their molecules. Full exploitation of aromatic dipole moments, C-H hydrogen bonding, halogen bonds, and pi-pi interactions is only possible by understanding the electrostatic basis of these effects. Consideration of the protein electrostatics can inform ligand design to generate complementary patterns of electron rich and electron poor regions.

Putting electrostatics and water at the center of structure-based drug design

COMP poster 292

Tim Cheeseright, Director of Products, Cresset

The electrostatics of protein active sites can inform ligand design and SAR. However, no calculation of electrostatic potentials in the active site can be complete without also considering whether water molecules are tightly bound and contributing to the potentials and ligand binding. In this poster we will explore the effect of including water molecules shown to be energetically favorable on the electrostatic potential of individual proteins. We will present a new application to enable rapid and accurate calculation of water stability and protein interaction potentials. Combining these analyses with the popular Waterswap technique results in an in-depth knowledge of protein targets and ligand protein binding.

Combining protein interaction potentials with water analysis in structure-based design

COMP oral 497

Tim Cheeseright, Director of Products, Cresset

The XED molecular mechanics force field is unique in providing off-atom centered charges that enable studying complex charge distributions in ligands and proteins alike. We have previously described the use of the molecular interaction potentials derived from the XED force field for ligand similarity calculations which have, in turn, enabled virtual screening, scaffold hopping and SAR analysis to be performed using these effective and meaningful descriptors. In this talk we will describe in detail our application of the XED force field to proteins. We will focus on the calculation of protein interaction potentials showing how protein electrostatics provide deep insights into ligand binding that would otherwise be missed. In parallel to the calculation of the protein interaction potentials we describe using XED to minimize protein-ligand complexes and demonstrate the synergy between these methods.

Understanding protein-ligand binding at the molecular level: Using swap-based methods to visualise binding free energy components

COMP oral 103

Christopher Woods, University of Bristol

Binding free energy methods allow computational chemists to predict whether or not changes to a ligand increase or decrease its binding affinity to a medicinally important protein. While these methods can reveal whether or not a change to the ligand increases its binding affinity, they provide little information as to how this change affects individual molecular interactions. Such information would be extremely useful, as it could provide feedback to a drug designer that could inspire the next series of ligand modifications. For example, it would be valuable for the free energy calculation to reveal that addition of a hydroxyl group to a ligand strengthens its interaction with an active site aspartate residue, but simultaneously destabilises a water molecule that bridges between it and the protein. This feedback could inspire a drug designer to investigate ligand modifications that combine addition of the hydroxyl group with the addition of moeities that displace the bridging water molecule. We have developed a range of binding free energy methods, based on WaterSwap. These swap-based methods allow calculation of absolute and relative protein-ligand binding free energies using a single simulation over a single λ-coordinate. Use of a single coordinate allows components of the binding free energy (i.e. specific interactions between the ligand and individual active-site residues, or between the ligand and neighbouring water molecules) to be integrated across λ during the simulation. The resulting components are used to colour-code 3D views of the proteinligand system. This allows drug designers to easily visualise the affect of ligand modifications on the interactions between the ligand and individual residues in the protein, and individual water molecules in the binding site. These components are not true free energies. However, what they reveal is chemically intuitive, and provide a level of insight that allows drug designers to suggest modifications that lead to improved binding affinity. The components show cooperative affects, and also reveal how increasing the strength of interaction

Visualising the molecular drivers behind drug resistance

COMP Sci-Mix poster 347

Christopher Woods, University of Bristol

The huge expense of developing a new drug can be wasted if natural mutations of amino acid residues in the targetted protein lead to a loss of drug binding affinity. Rational drug design is a continual struggle, with evolution driving mutations that develop emerging drug resistance into widespread drug inefficacy. We have developed a new free energy method, based on WaterSwap, that can provide drug designers with the insight needed to understand how protein mutations affect drug binding. This method allows the change in binding free energy of the drug associated with the mutation of the protein to be predicted. In addition, as for other Swap-Based methods, this free energy change can be decomposed into components that can be used for visualisation. These components allow the change in binding free energy to be understood in terms of changes in specific ligand-protein interactions, or changes in the solvating water network in the active site. This method allows drug designers to pro-actively screen a new drug computationally against a range of likely protein mutants, thereby enabling the drug designer to get one step ahead of nature. Alternatively, it allows drug designers to investigate the molecular basis for reduced binding affinity in known drug-resistant mutants of a protein. This information would be useful for the development of the subsequent generations of the drug.

March 2017 newsletter

Flare sneak peek

Take a sneak peek at Flare, our new structure-based design application. See how the innovative features and new science combine to give you new insights into structure-based design.

Blaze used in discovery of allosteric modulators of the high affinity choline transporter

Scientists from Pfizer, Neusentis, Nanion, and Kissei have identified 9 new active small molecules that modulate the pathway of interest. 5 of these were identified from the Pfizer corporate compound library using a set of 887 compounds chosen using Cresset’s Blaze virtual screening software.

Cresset signs strategic alliance agreement to speed up drug design

Our collaboration with the school of Pharmaceutical Sciences, Sun Yat-Sen University, and iPrecision Medicine Technology Inc., brings together expertise and innovation in development technologies for computational molecule design.

Spark reagent databases

Get the very best availability information on which reagents to order. Download the March release of the Spark reagent databases using the Spark Database update widget (instructions on the installing Spark databases page), or contact us if you would like to use a command line utility (such as wget).

Tips and tricks

  • Setting up a FieldTemplater experiment
  • Merging structure and activity files
  • Rigid-body ligand alignment
  • See all tips and tricks.

Meet us in April

  • April 1st: COMP Saturday Social with CINF, CA, USA co-sponsored by Cresset
  • April 2nd – 6th: ACS, San Francisco, CA, USA. Cresset applications will feature in the following oral/poster presentations:
    • Improving new molecule design using electrostatics
    • Putting electrostatics and water at the center of structure-based drug design
    • Combining protein interaction potentials with water analysis in structure-based design
    • Understanding protein-ligand binding at the molecular level: Using swap-based methods to visualise binding free energy components
    • Visualising the molecular drivers behind drug resistance
  • April 24th – 27th: Drug Discovery Chemistry, San Diego, CA, USA
    • Meet David Bardsley at booth 404 for a preview of Flare, our new structure-based design application

Have you registered for The Cresset User Group Meeting?

June 29th, Scientific program

Join us to hear speakers from 4 continents share their use of Cresset applications on topics including fragment library design, protein-ligand binding, virtual screening and fragrance molecule design. We will showcase Flare, our exciting new structure-based design application, give an update on our ligand-based tools and a peek into the heart of new Cresset science.

June 30th, Hands-on software workshops

  • Introduction to Flare for computational, medicinal and synthetic chemists
  • SAR with Forge
  • Spark: Introduction and advanced
  • Virtual screening with Cresset
  • 3D-QSAR
  • Torch

Find out more and register.

Cresset signs strategic alliance agreement to speed up drug design

Cambridge, UK – 28 March 2017 – Cresset, innovative provider of software and contract research services for small molecule discovery and design, signs three-way strategic agreement to speed up drug design.

Dr David Bardsley, Commercial Director, Cresset visited the School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China to sign a strategic cooperation agreement for drug design technology, developed within the Research Centre for Drug Discovery (RCDD). This visit was in response to an invitation from Professor Jun Xu, RCDD, and was hosted by Mr Wenhao Hu, Dean of the School, and Huichang Bi, Vice Dean of the School for International Development.

A further agreement was signed between Dr Bardsley and Mr DeKang Zhang, Chairman, iPrecison Medicine Technology Inc., whereby Cresset will promote iPrecision software and technology globally. This agreement follows the transfer of 10 drug design software patents from RCDD to iPrecision last year.

“This British-Chinese three-way agreement brings together expertise and innovation in development of technologies for computational molecule design”, says Dr Bardsley, Cresset. “I look forward to working with each organization to establish global distribution channels.”

Back row, left to right: Huichang Bi, Professor Jun Xu, DeKang Zhang, Zhishu Huang

Front row: left to right: Mr Wenhao Hu, Dr David Bardsley

Left to right: Huichang Bi, Dr David Bardsley, Mr Wenhao Hu, DeKang Zhang, Professor Jun Xu, Zhishu Huang

 

February 2017 newsletter

Case study: Conduct ligand-protein docking

Find out how we conducted ligand-protein docking to narrow down a 50k compound library to the best 1.5k compounds at a fraction of the cost of buying and screening the entire 50k library.


RDKit molecular simulations through OpenMM

Paolo Tosco describes how RDKit is used in Cresset software and presents preliminary work on boosting RDKit molecular simulations through OpenMM.
 
 


Web clip tips and tricks

  • Changing preferred alignments
  • Importing pre-existing conformations
  • Using Tags to organize data sets

See more tips and tricks.


Flexible licensing terms for academics

Cresset support the academic community through flexible licensing terms. Licenses have been created specifically to facilitate academic research and teaching within a university.


Cresset User Group Meeting, 29-30 June – workshop spaces limited

The day after the scientific program we will hold hands-on software workshops – spaces are limited so early registration is encouraged.