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A ligand’s-eye view of protein binding

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Abstract

Docking tools created for structure-based design and virtual screening have also been used to automate ligand alignment for comparative molecular field analysis (CoMFA). Models based on such alignments have been compared with those obtained based solely on shared ligand substructures, but such comparisons have generally failed to distinguish between conformational specification (alignment in the internal coordinate space) and embedding in a shared external frame of reference (Cartesian alignment). Here, large sets of inhibitors were docked into two cyclooxygenase and two reverse transcriptase crystal structures, and the poses generated were evaluated in terms of the CoMFA models they produced. Realigning the conformers obtained by docking by rigid-body rotation and translation to overlay their common substructures improved model statistics and interpretability, provided the protein structure used for docking was reasonably appropriate to the ligands being considered.

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Notes

  1. For the systems considered here and other similar ones, CoMFA and CoMSIA generally yield quite similar results. In the interests of simplicity, only CoMFA results are described here, but similar conclusions should hold true for CoMSIA.

  2. Their compound 18.

  3. The Research Collaboratory for Structural Bioinformatics (http://www.rcsb.org/pdb).

  4. The FCC lattice is generated by nesting one cubic lattice inside another, offset by a half step along each axis. The TAILOR AUTO_REGION LATTICE and TAILOR AUTO_REGION STEP_SIZE commands controls the relevant settings in SYBYL.

  5. Here, “regression weight” is defined as the product of the regression coefficient and the standard deviation of the field at each lattice point.

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Acknowledgments

Drs. Richard Cramer and Brian Masek of Tripos International provided helpful discussions in the work described here. Drs. Ajay Jain (UCSF) and Essam Metwally (Tripos International) have been invaluable collaborators with respect to the Surflex-Dock.

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    Robert D. Clark

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Clark, R.D. A ligand’s-eye view of protein binding. J Comput Aided Mol Des 22, 507–521 (2008). https://doi.org/10.1007/s10822-008-9177-8

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