Enhancements to the Rosetta Energy Function Enable Improved Identification of Small Molecules that Inhibit Protein-Protein Interactions.
Protein-protein interactions are among today's most exciting and promising targets for therapeutic intervention. To date, identifying small-molecules that selectively disrupt these interactions has proven particularly challenging for virtual screening tools, since these have typically been optimized to perform well on more "traditional" drug discovery targets. Here, we test the performance of the Rosetta energy function for identifying compounds that inhibit protein interactions, when these active compounds have been hidden amongst pools of "decoys." Through this virtual screening benchmark, we gauge the effect of two recent enhancements to the functional form of the Rosetta energy function: the new "Talaris" update and the "pwSHO" solvation model. Finally, we conclude by developing and validating a new weight set that maximizes Rosetta's ability to pick out the active compounds in this test set. Looking collectively over the course of these enhancements, we find a marked improvement in Rosetta's ability to identify small-molecule inhibitors of protein-protein interactions.
Center for Computational Biology, University of Kansas, 2030 Becker Dr., Lawrence, Kansas, 66045-7534, United States of America.
Andrea
A
Bazzoli
Center for Computational Biology, University of Kansas, 2030 Becker Dr., Lawrence, Kansas, 66045-7534, United States of America.
Simon P
SP
Kelow
Center for Computational Biology, University of Kansas, 2030 Becker Dr., Lawrence, Kansas, 66045-7534, United States of America; Department of Molecular Biosciences, University of Kansas, 2030 Becker Dr., Lawrence, Kansas, 66045-7534, United States of America.
John
J
Karanicolas
D055808:Drug Discovery / Q000379:methods*; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D060066:Protein Interaction Maps / Q000187:drug effects*; D017434:Protein Structure, Tertiary; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D013816:Thermodynamics
D054852:Small Molecule Libraries