6c7i › Citations

Mathematical and Structural Characterization of Strong Nonadditive Structure-Activity Relationship Caused by Protein Conformational Changes.

Gomez L, Xu R, Sinko W, Selfridge B, Vernier W, Ly K, Truong R, Metz M, Marrone T, Sebring K, Yan Y, Appleton B, Aertgeerts K, Massari ME, Breitenbucher JG
J Med Chem 61 7754-7766 (2018)
Related entries: 6c7d, 6c7e, 6c7f, 6c7g, 6c7j

Cited: 7 times
EuropePMC logo PMID: 30070482

Abstract

In medicinal chemistry, accurate prediction of additivity-based structure-activity relationship (SAR) analysis rests on three assumptions: (1) a consistent binding pose of the central scaffold, (2) no interaction between the R group substituents, and (3) a relatively rigid binding pocket in which the R group substituents act independently. Previously, examples of nonadditive SAR have been documented in systems that deviate from the first two assumptions. Local protein structural change upon ligand binding, through induced fit or conformational selection, although a well-known phenomenon that invalidates the third assumption, has not been linked to nonadditive SAR conclusively. Here, for the first time, we present clear structural evidence that the formation of a hydrophobic pocket upon ligand binding in PDE2 catalytic site reduces the size of another distinct subpocket and contributes to strong nonadditive SAR between two otherwise distant R groups.

Articles citing this publication (7)

  1. Nonadditivity in public and inhouse data: implications for drug design. Gogishvili D, Nittinger E, Margreitter C, Tyrchan C. J Cheminform 13 47 (2021)
  2. Editorial Decision Making in Medicinal Chemistry: The Power of Our Intuition. Gomez L. ACS Med Chem Lett 9 956-958 (2018)
  3. Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors. Ritawidya R, Ludwig FA, Briel D, Brust P, Scheunemann M. Molecules 24 E2791 (2019)
  4. Design, Synthesis, and Biological Evaluation of Novel 6H-Benzo[c]chromen-6-one Derivatives as Potential Phosphodiesterase II Inhibitors. Tang L, Jiang J, Song G, Wang Y, Zhuang Z, Tan Y, Xia Y, Huang X, Feng X. Int J Mol Sci 22 5680 (2021)
  5. Implications of Additivity and Nonadditivity for Machine Learning and Deep Learning Models in Drug Design. Kwapien K, Nittinger E, He J, Margreitter C, Voronov A, Tyrchan C. ACS Omega 7 26573-26581 (2022)
  6. Radiosynthesis and Biological Investigation of a Novel Fluorine-18 Labeled Benzoimidazotriazine- Based Radioligand for the Imaging of Phosphodiesterase 2A with Positron Emission Tomography. Ritawidya R, Wenzel B, Teodoro R, Toussaint M, Kranz M, Deuther-Conrad W, Dukic-Stefanovic S, Ludwig FA, Scheunemann M, Brust P. Molecules 24 E4149 (2019)
  7. 3-Arylidene-2-oxindoles as GSK3β inhibitors and anti-thrombotic agents. Babkov D, Bezsonova E, Sirotenko V, Othman E, Klochkov V, Sosonyuk S, Lozinskaya N, Spasov A. Bioorg Med Chem Lett 87 129283 (2023)


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