ACS Denver 2015: Scaffold hopping: Balancing novelty, accessibility and physico-chemical properties

Scaffold hopping remains a central task in medicinal chemistry for generating and protecting intellectual property. We have previously presented a technique for rapidly generating reasonable yet novel scaffold replacements using molecular fields which has been extended to include R-group replacement. The approach uses a database of molecule fragments or available reagents to suggest replacements that maintain the shape and electrostatic character of a known active molecule.

However, for both of scaffold hopping and R-group replacement activity is not the only requirement for any suggested replacement. To be useful they must be synthetically accessible and must fall within the window of acceptable physicochemical properties for the project. The task of ranking scaffold hops or bioisosteric replacements is thus one of multi-parameter optimization, where several often-competing requirements have to be considered simultaneously.

In this poster we suggest methods to address these issues with reference to case studies of both scaffold hops and R-group replacements. Synthetic accessibility can be handled by tying the bioisostere search to addressable chemistry space, utilizing the chemist’s knowledge of what synthetic routes are feasible to guide the search. The best guide of novelty in a scaffold-hopping situation is the experience of the user: what other scaffold are known in the literature or in patents? To this end, we suggest a clear and minimal user interface to allow rapid triage of large result lists. Finally, assessing results in the light of physicochemical and predicted ADMET requirements can be achieved through a configurable radar plot giving clear visual feedback on how close any suggested replacement is to the ideal.

Click image to see poster.

ACS Denver 2015 Scaffold hopping Balancing novelty accessibility and physico-chemical properties

Presentations from 248th ACS National Meeting and Exposition

The following were presented at the 248th ACS National Meeting and Exposition in San Francisco.

Find out more about Cresset’s software, consulting services and download a free software demo.

Contact us if you would like to discuss the content of these presentations.

Presentations from Field Based Chemistry North America 2013

Our thanks goes to the following speakers who contributed to making this event such a success:

      Rajeshri Karki, Novartis
      Patrick McCarren, The Broad Institute
      Alfred M Ajami, DCAM Pharma Inc.
      Daniel Barr, Utica College
      Simon Cocklin, Drexel University

The following presentations have been made available by permission of the presenter. Click the talk title to view the presentation.

Using field based chemistry methods to understand sequence-specific protein-DNA interactions

        Daniel Barr, Utica College

Drug hunts with Spark: case studies from the literature and current campaigns to develop immunokinase inhibitors

    Alfred M Ajami, DCAM Pharma Inc.

To be informed about Field Based Chemistry 2014, and other Cresset events, sign-up for our newsletter.

Cresset to Exhibit and Present at American Chemical Society National Meeting and Exposition

Welwyn Garden City, UK (28th May 2012) Cresset, innovative provider of software and services for molecule designers, will be exhibiting on booth 409 at the American Chemical Society (ACS) National Meeting and Exposition which takes place in Philadelphia, PA, USA on August 19th – 23rd 2012.

Cresset will also be presenting as follows:

Computation Tools for Medicinal Chemists: Increasing the Dimensions of Drug Discovery
by Dr Robert Scoffin, Chief Executive Officer
Session: When Chemists and Computers Collide: Putting Cheminformatics in the Hands of Medicinal Chemists
August 19, 2012 from 10:15 am to 10:45 am; Philadelphia Marriott Downtown, Room 302/303

Identifying Novel Bioisosteres
by Dr Tim Cheeseright, Director of Products
Session: Bioisosteres Redux: Strategic Deployment in the Design and Development of Drug Candidates
August 22, 2012 from 9:10 am to 9:50 am; Pennsylvania Convention Center, Room Ballroom IV

Optimizing your Leads for Potency AND Drug-Likeness – How To Have It All
by Dr Robert Scoffin, Chief Executive Officer
Session: Optibrium StarDrop User Group and Workshop
August 22, 2012 from 12:00 pm to 14:30 pm; Pennsylvania Convention Center, Room 202A

Disruptive Technology for Chemical Patent Fortification
by Dr Rae Lawrence, Technical Sales Manager
Session: The Many Faces of CHAL: Where Chemistry Meets the Law
August 23, 2012 from 4:25 pm to 4:50 pm; Pennsylvania Convention Center, Room 113 C

Cresset CEO, Dr Robert Scoffin, said, “We are delighted to be participating in this event again. The ACS national meeting attracts chemists from around the world and enables them to learn about cutting edge technologies, such as our range of next generation chemistry software and services. Each of our presentations will present thought-provoking and enlightening methods for research. We hope to see you there to demonstrate how Cresset’s tools can set your company on the fast track to novel chemistry.”

Meeting the needs of computational and medicinal chemists, Cresset’s suite of next generation chemistry software comprises: forgeV10 a powerful computational suite to understand SAR and design; torchV10 an intuitive design and 3D SAR tool for medicinal chemists; torchV10lite a free 3D molecule viewing, editing and drawing tool; blazeV10 an amazing ligand based virtual screening tool; sparkV10 an exciting and powerful way of generating novel and diverse structures.

Scientists interested in Cresset’s next generation software can download free demos from the company’s website.

For further information on the complete range of software and services available from Cresset, please visit us on booth 409 at the ACS National Meeting and Exposition, visit cresset-group.com, follow Cresset on Twitter (@cressetgroup) or join the LinkedIn group.

ACS San Diego: Cresset presentation now available

If you missed joining us at ACS San Diego in March, you’ll have another chance to say hello in August when we attend the next ACS meeting in Philadelphia. In the interim, we are delighted to share an ACS San Diego presentation given by our very own Dr. Tim Cheeseright.   In this presentation, Tim investigates alternative methods of defining 3D chemical space, and shares the value that molecular fields can add to projects.

Assessing the similarity of compound collections using molecular fields: Does it add value?

Abstract. The application of chemical diversity in the discovery of novel drug molecules is a contentious issue. The way in which chemical space is often defined – and thus sampled effectively – is by using the 2D connectivity maps of atoms within molecules. These maps can be encoded as numbered features which can be counted and compared. Although this is a particularly effective method on a large scale it has deficiencies. These largely spring from what fundamentally underpins the interaction of a molecule with its biological target, which is not related to the 2D chemical framework but to the 3D interaction of the surface of the molecule via shape and field complementarity. We have investigated alternative methods of defining chemical space using 3D Field based methodologies – the advantages and disadvantages of which we will describe.

View more presentations from Cresset.

Questions about this presentation?  Contact us for further details and discussion, or register to attend one of our free user group meetings for training.  We have two meetings in the next few months, so click the links below for more information and registration.

North American User Group Meeting
Location: Cambridge, MA, USA
Date: May 18, 2012

European User Group Meeting
Location: Cambridge, UK
Date: June 20-21, 2012

April 2012 Newsletter

Register for Cresset NA User Meeting on May 18

Our North American User Meeting is approaching fast and has only limited spaces. We’ve got free training on our new Forge application, excellent speakers, a new product to show, and we’re still adding to the agenda.

Register now to avoid disappointment


Design Competition Closes April 30

Our fourth design a molecule challenge has again been very popular and now we are giving you just a little longer to get your entries submitted. Already registered – you’ll need a new license file from here. Not registered yet – no problem, you can do it now. We’ve got an introductory video and a full training video to help you get the best molecule that you can.

Design a Molecule and win an iPad, see more.


Sneak Peak at Molecular Forge

We’ve been talking about our new application for a while but it is now very close to release. Along with a new look and lots of new functionality we have a new name – Forge. We hope the capabilities that we’ve introduced will help you knock some sense into your data and help you make something new and shiny!

See Forge in action here.


Meet in Tucson or Elsewhere

We’re attending and exhibiting the National Medicinal Chemistry Symposium in Tucson, AZ, May 20-23 but that is not the only place you can meet us this year. If you missed us at the ACS in San Diego then maybe Philidelphia in August would suit you better? We’re also planning our trip to Vienna for the EuroQSAR as well as polishing the speaker list for our own meeting in June. How about you?

Learn more about Cresset events here.


Teach-Discover-Treat

Cresset is proud to be sponsoring an award under the Teach-Discover-Treat initiative of the COMP division of the ACS. The initiative is aimed at delveloping cutting edge workflows that can be used for teaching and pro-actively in the discovery of active molecules. The initiative takes the form of a competition – put together the best workflow under one of 4 categories and win a trip to the ACS in New Orleans.

Learn more from TDT’s website.


Follow cressetgroup on TwitterJoin the Cresset Group on LinkedIN

Cresset ACS Spring 2012- ‘The Chemistry of Life’

We’re looking forward to another great event at the ACS Spring 2012 National Meeting in San Diego, March 25 – 29, 2012.  We encourage delegates to visit us at booth 1837 for a chance to enter the latest Design a Molecule competition and meet the Cresset team.  This event will be attended by North American Sales Manager Rae Lawrence, CEO Rob Scoffin, and Products Director Tim Cheeseright; each of whom can provide you with expert advice and information about Cresset software and services.

In addition to our exhibition booth, you can find Cresset in the Division of Computers in Chemistry, where we will be attending several sessions.   Tim Cheeseright is participating in the Drug Discovery session on March 29th at 11:15AM, giving a presentation on the advantages and disadvantages of 3D field based methodologies in drug discovery.  The presentation is in the San Diego Convention Centre in room 28E and attendance is included in the registration of ACS delegates so we encourage you to join the audience to learn a little more about Cresset technology.    Please find the presentation abstract below.

Assessing the Similarity of Compound Collections using Electrostatics and Shape, Does it Add Value?

The application of chemical diversity in the discovery of novel drug molecules is a contentious issue.  It can be argued that true chemical diversity has little relevance to the discovery of drugs. For instance, oral drugs have to adhere to a particular physiochemical profile in order for them to be absorbed and distributed effectively to their biological target.  The chemical space associated with oral drugs is thus reduced to a smaller region of the theoretical space.  However, practically even this reduced chemical space is still difficult to explore effectively without employing methods which reduce redundancy as much as possible.  The way in which chemical space is often defined and thus sampled effectively, is by using the 2D connectivity maps of atoms within molecules. These maps can be encoded as numbered features which can be counted and compared.  Although this is a particularly effective method on a large scale it has deficiencies.  These largely spring from what fundamentally underpins the interaction of a molecule with its biological target, which is not related to the chemical framework but to the 3D interaction of the surface of the molecule via shape and field complementarity.  We have investigated alternative methods of defining chemical space using 3D Field based methodologies – the advantages and disadvantages of which we will describe.

ACS Fall 2011 National Meeting and Exhibition: Air, Space and Water

Cresset is pleased to take part in the American Chemical Society’s 242nd National Meeting & Exhibition this August 28th – September 1st.   Come find us at booth 1817 to learn more about the latest product development, meet the Cresset team, and enter our third Design a Molecule contest for a chance to win an iPad2!  This popular contest give entrants a chance to design a molecule that best matches a specific target using Cresset’s Field Align Software.  Contestants receive free access to the software for the duration of the contest and the designer of the best molecule (as determined by FieldAlign Score) will win an iPad2.  Contest opens August 25th, so come visit us at booth 1817 to enter or click here for details.

The National Meeting program includes  a wide range of excellant presentations, including four lectures from our very own Cresset scientists.   The topic of each presentation is listed below, so make note of the times and locations to attend.

Towards Automated 3D-QSAR:Using Unbiased Alignment of Structures and Non Grid-Based Descriptor Generation on a Series of Human NK3 Inhibitors

Date/Time: Tuesday, August 30, 2011 9AM, Drug Discovery Session

Location: Colorado Convention Centre, Room 302

Presenter: Dr. Rob Scoffin

Abstract: We present details of the development and application of a novel 3D-QSAR approach with the potential to be fully automated. Our method introduces an unbiased molecular alignment step and a non grid-based mechanism for generation of 3D descriptors to avoid some of the key issues inherent with existing approaches. Using an automated molecular alignment step significantly reduces the bias present in existing manual alignments. Descriptors are created at key points on the surface of the ligands under study rather than using a grid, removing key variables (grid spacing and molecular orientation) in 3D QSAR production. Analysis is carried out using PLS, and results are able to be related back to the changes in molecular structure across the series. Validation of the method using literature datasets and application to a prospective novel series of inhibitors of Neurokinin-B (NK-3) receptor inhibitors will be presented.

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Conformation Searching and the Limits of Conformation Space

Date/Time: Thursday, September 1st, 2011, 9AM, Drug Discover Session

Location: Colorado Convention Center, Room 302

Presenter: Dr. Mark Mackey

Abstract: We present the results of an in-depth assessment of the XedeX conformer searching protocol. XedeX was designed to give conformational diversity within a relatively limited number of conformations, rather than attempting an exhaustive enumeration of conformation space. The algorithm has a number of tuneable parameters including the number of conformers desired, whether a full or partial force field minimisation should be used, the similarity threshold for deciding whether two conformers are different, and whether a torsional threshold for conformer similarity should be included. An extensive analysis of all of these factors on a large database of known bioactive conformations is presented, with results indicating that the optimal conditions for relatively rigid and relatively flexible molecules differ in surprising ways. A fundamental relationship between conformation search performance (as it is usually assessed) and the average number of conformers generated is shown. Finally, the existing literature data sets for assessing conformation search performance are discussed and an improved version provided.

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Evaluating bioisosteric replacements taking the whole molecule into account

Date/Time: Thursday, September 1st, 2011, 1:30 PM, Drug Discover Session

Location: Colorado Convention Center, Room 302

Presenter: Dr. Mark Mackey

Abstract: Bioisosterism is an important concept in  medicinal chemistry, and the ability to quickly change key parts of a lead molecule without affecting its biological properties is highly desirable. A number of systems for identifying or searching for bioisosteres have been described, but most of these focus on assessing the similarity of the isosteric groups in isolation, ignoring their environment. We describe a new method, FieldStere, which solves this problem. In FieldStere, an active ligand is loaded and a region to be replaced is identified. FieldStere searches a fragment library for replacements that can fit the required vectors. Each proposed replacement is merged into the original ligand, and the entire new molecule’s similarity to the original ligand is assessed using shape and electrostatic properties. The use of product-based scoring allows the steric and electronic influences of the proposed replacement on the rest of the molecule to be assessed as part of the score.  The use of FieldStere in finding new bioisosteres for a number of targets will be presented together with a critique of the current quantitative assessment methods and some proposals for how this may be measured more meaningfully.