Article by the K-Ras has isAmerican apublished potential Chemical Society. 1155 Sixteenth allosteric Streetsmall N.W., Washington, DC 20036 molecule binding site Published by American G12D
Chemical Society. Subscriber access provided by UNIV Copyright © American AUTONOMA DE COAHUILA UADEC Chemical Society. However, no copyright
Huizhong Feng, Yan Zhang, Pieter H. Bos, Jennifer M. is published by the Chambers, Marcel M.Chemical Dupont, American Society. 1155 Sixteenth and Brent R. Stockwell
Street N.W., Washington,
DC 20036 Biochemistry, Just Accepted Published by American Manuscript • DOI: 10.1021/
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acs.biochem.8b01300 • Publication Date (Web): 01 May 2019 published by the Downloadedisfrom http:// American Chemical pubs.acs.org on May1155 2, 2019 Society. Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Subscriber access provided by UNIV Copyright © American AUTONOMA DE COAHUILA UADEC Chemical Society. However, no copyright
Just Accepted
is published by the “Just Accepted” manuscripts have been pe American Chemical online prior to technical editing, formatting f Society. 1155 Sixteenth Washington, Society provides Street “JustN.W., Accepted” as a servic DC 20036 of scientific material as soon as Published by American possible Chemical Society. full in Subscriber PDF format accompanied by an HT access provided by UNIV Copyright © American AUTONOMA DE COAHUILA UADEC Chemical Society. However, no copyright
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OH
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N
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Glide Docking Score: -7.37 Chemical Formula: C21H31N3O2 Molecular Weight: 357.50
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Biochemistry OH
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Next, we performed a molecular dynamics (MD) simulation to mimic different conformations of K-RasG12D other than the ones found in the crystal structures. 20 clusters were generated from a 200 ns MD simulation. The P110 site appeared consistently in these simulations, of which one cluster (#6) showed the best SiteMap score of 1.06 (Figure S1D). This suggests that this pocket can become even more accessible during motion of the K-RasG12D protein. Mixed Solvent Molecular Dynamics (MxMD) simulations were then run with structure 4DSN using acetonitrile, isopropanol, pyrimidine, acetone, imidazole, and Nmethylacetamide as organic probes. These organic probes can affect the conformation of K-RasG12D and reveal which sites can be accessible to small molecules of various
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chemotypes23. The P110 site was found to contain all of these solvents as a hot spot, indicating its potential as binding pocket for small organic molecules (Figure S1E). We evaluated whether we could identify fragments or lead-like compounds predicted to bind with reasonable affinity to the P110 site. We tested 3.5 million compounds using the Glide docking algorithm (Schrödinger Suites), which generates a score in which the more negative the score, the higher the predicted affinity24. 77 fragments with scores
