Comparative Molecular Moment Analysis (CoMMA):  3D-QSAR without Molecular Superposition

B. D. Silverman* and Daniel. E. Platt
IBM Thomas J. Watson Research Center, Yorktown Heights, New York 10598
J. Med. Chem., 1996, 39 (11), pp 2129–2140
DOI: 10.1021/jm950589q
Publication Date (Web): May 24, 1996
Copyright © 1996 American Chemical Society
*

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

Abstract

3d-QSAR procedures utilize descriptors that characterize molecular shape and charge distributions responsible for the steric and electrostatic nonbonding interactions intimately involved in ligand−receptor binding. Comparative molecular moment analysis (CoMMA) utilizes moments of the molecular mass and charge distributions up to and including second order in the development of molecular similarity descriptors. As a consequence, two Cartesian reference frames are then defined with respect to each molecular structure. One frame is the principal inertial axes calculated with respect to the center-of-mass. For neutrally charged molecular species, the other reference frame is the principal quadrupolar axes calculated with respect to the molecular “center-of-dipole”. QSAR descriptors include quantities that characterize shape and charge independently as well as quantities that characterize their relationship. 3D-QSAR partial least squares (PLS) cross-validation procedures are utilized to predict the activity of several training sets of molecules previously investigated. This is the first time that molecular electrostatic quadrupolar moments have been utilized in a 3D-QSAR analysis, and it is shown that descriptors involving the quadrupolar moments and related quantities are required for the significant cross-validated predictive r2's obtained. CoMMA requires no superposition step, i.e., no step requiring a comparison between two molecules at any stage of the 3D-QSAR calculation.

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History

  • Published In Issue May 24, 1996
  • Received August 7, 1995

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