ChemRxiv
These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
1/1
2 files

Identification and Analysis of Activity Cliffs Using 3D Similarity Techniques

preprint
submitted on 18.09.2020 and posted on 21.09.2020 by Mark Mackey, Timothy J. Cheeseright, Paolo Tosco

The analysis of activity landscapes and activity cliffs is a widely used method to locate critical regions of SAR. Knowledge of what changes in a series of molecules caused unexpectedly large changes in affinity allows the chemist to focus on the molecular features which are crucial for activity. We examine the usefulness of activity cliff analysis with a metric based on 3D shape and electrostatic similarity, utilizing a ligand-based alignment method. We demonstrate that 3D activity cliff analysis is complementary to the more usual 2D fingerprint-based methods, in that each finds cliffs that the other misses. Moreover, we show that analysis of the activity landscape in the context of a consensus 3D alignment allows the source of the activity cliff to be investigated in terms of the effect that a structural change has on the steric and electrostatic properties of a molecule. The technique is illustrated with two set of compounds with activity against acetylcholinesterase and dipeptidyl peptidase.

History

Email Address of Submitting Author

mark@cresset-group.com

Institution

Cresset

Country

United Kingdom

ORCID For Submitting Author

0000-0001-5131-7583

Declaration of Conflict of Interest

Tha authors are employees of and shareholders in Cresset

Version Notes

Initial chemrxiv release (version 15)

Exports