Accurate and efficient bioactive conformational searching

The Advantage of Efficient Conformational Searching

Conformer generation is useful in many aspects of both molecular modeling in general and drug discovery in particular. The relative energies of small molecule conformations play a crucial role in determining the shape, function, and activity. Moreover, the ability to generate a bioactive conformer is a vital prerequisite to any successful computer-aided drug design project.

While it's impossible for a conformer search algorithm to determine a flexible ligand's bioactive conformer with absolute confidence, carefully considered search criteria do allow an algorithm to reject conformers likely to be high energy or inactive. Beyond merely expediting the conformer search process, this approach creates efficiently sized conformer sets that nevertheless contain a reasonable approximation of the bioactive geometry.

Efficient conformer sets have wide-ranging ramifications in downstream applications. For example, with fewer irrelevant conformations to process, virtual database screens and shape-based similarity searches run to completion in a fraction of the time without sacrificing accuracy.

Learn more about ConfGen by reading our white paper.

An optimal combination of physics and heuristics:
Built-in chemical knowledge and well-validated training of the program allow ConfGen to forego unnecessary search steps. Accurate force-field-based calculations, including minimizations, or rapid, systematic variations allow ConfGen to identify local torsional minima as dictated on a case-by-case basis.

Well-validated preset options:
Considerable development work has been focused on the creation of a basic interface that allows users to choose from several pre-configured combinations of these settings. Although ConfGen's advanced interface affords full control over many individual settings, the options used in the basic interface are thoroughly validated, and allow users to choose a project-appropriate compromise between speed and accuracy with no guesswork involved.

Broad coverage of ligand conformational space:
Because ConfGen performs more than just isolated local sampling, the resulting conformer sets include a variety of extended conformations, which tend to be characteristic of bioactive conformers.

Distributed processing support:
Submitting a distributed ConfGen calculation is as simple as checking a box next to the remote hosts or the queue you wish to use, allowing you to make maximum use of your lab's computational resources.

Citations and Acknowledgements

Schrödinger Release 2023-3: ConfGen, Schrödinger, LLC, New York, NY, 2023.

ö Watts, K.S.; Dalal, P.; Murphy, R.B.; Sherman, W.; Friesner, R.A.; Shelley, J.C., "ConfGen: A Conformational Search Method for Efficient Generation of Bioactive Conformers," J.Chem. Inf. Model., 2010, 50, 534-546

"Benchmarking Commercial Conformer Ensemble Generators"

Friedrich, N.; de Bruyn Kops, C.; Flachsenberg F.; Sommer, K.; Rarey, M.; Kirchmair, J., J. Chem. Inf. Model., 2017, Article ASAP, DOI: 10.1021/acs.jcim.7b00505

· "Exploring Conformational Search Protocols for Ligand-based Virtual Screening and 3-D QSAR Modeling"

Cappel, D.; Dixon, S.L.; Sherman, W.; Duan, J., J. Comput. Aided Mol. Des., 2015, 29(2), 165-182

"Optimization, Pharmacophore Modeling and 3D-QSAR Studies of Sipholanes as Breast Cancer Migration and Proliferation Inhibitors"

Foudah, A.I.; Sallam, A.A.; Akl, M.R.; El Sayed, K.A., Eur. J. Med. Chem., 2014, 73, 310-324

"Bioguided discovery and pharmacophore modeling of the mycotoxic indole diterpene alkaloids penitrems as breast cancer proliferation, migration, and invasion inhibitors"

Sallam, A.A.; Houssen, W.E.; Gissendanner, C.R.; Orabi, K.Y.; Foudah, A.I.; El Sayed, K.A., Med. Chem. Commun., 2013, 4, 1360-1369

· "Improved docking of polypeptides with Glide"

Tubert-Brohman, I.; Sherman, W.; Repasky, M.; Beuming, T., J. Chem. Inf. Model., 2013, 53(7), 1689-1699

· "Boosting virtual screening enrichments with data fusion: Coalescing hits from two-dimensional fingerprints, shape, and docking"

Sastry, G.M.; Inakollu, V.S.; Sherman, W, J. Chem. Inf. Model., 2013, 53, 1531-1542

· "ConfGen: A Conformational Search Method for Efficient Generation of Bioactive Conformers"

Watts, K.S.; Dalal, P.; Murphy, R.B.; Sherman, W.; Friesner, R.A.; Shelley, J.C., J.Chem. Inf. Model., 2010, 50, 534-546

"Drug-like Bioactive Structures and Conformational Coverage with the LigPrep/ConfGen Suite: Comparison to Programs MOE and Catalyst"

Chen, I.; Foloppe, N., J.Chem. Inf. Model., 2010, 50, 822-839
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