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.