Aggregation-based inhibitors

The compounds with final high rank orders are then tested experimentally using inhibition assays. The number of compounds to test is generally limited by the monetary and time cost of the experimental assays. The assays can then be repeated in the presence of detergent, e.g., Triton X-100, as a first test to filter out promiscuous, aggregate-based inhibitors (46). The inhibitory effect of the active compounds can also be tested on similar enzymes to investigate the specificity of the compounds for the enzyme of interest (see Note 16). 

Goan, K.E., Maltby, D.A., Burlingame, A.L., and Shoichet, B.K (2009) Promiscuous aggregate-based inhibitors promote enzyme unfolding. Journal of Medicinal Chemistry, 52, 2067-2075. 

Goan, KE. and Shoichet, B.K. (2008) Stoichiometry and physical chemistry of promiscuous aggregate-based inhibitors. Journal of the American Chemical Society, 130, 9606-9612. 

From peptide to non-pepdde. 2. The de novo design of potent, non-peptidal inhibitors of platelet aggregation based on a benzodia-zepinedione scaffold. J. Am Chem Soc. 116 5077-5083. 

Med. Chem., 35, 4914 (1992). Potent Inhibitors of Platelet Aggregation Based Upon the Arg-Gly-Asp-Phe Sequence of Fibrinogen. A Proposal on the Nature of the Binding Interactions Between the Asp-Carboxylate of RGDX Mimetics and the Platelet GP Ilb/lIIa Recep-... 

Lindmark, S. G. Panzer-Knodle, N. S. Nicholson, B. B. Taite, A. K. Salyers, L. W. King, J. G. Campion, and L. P. Feigen, /. Med. Chem., 36, 1811 (1993). Potent In Vitro and In Vivo Inhibitors of Platelet Aggregation Based Upon the Arg-Gly-Asp-Phe Sequence of Fibrinogen. A Proposal on the Nature of the Binding Interactions Between the Arg-Guanidine of the RGDX Mimetics and the Platelet GP Ilb-IIIa Receptor. 

Tang, H., Zhao, H.-T., Zhong, S.-M., Wang, Z.-Y., Chen, Z.-F. Liang, H. (2012). Novel oxoisoaporphine-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase -induced beta-amyloid aggregation. Bioorg. Med. Chem. Lett, 22(6), 2257-2261. 

The discovery of inhibitors of fibrillogenesis has been hampered by the complexity of the folding pathway, the presence of mixed populations of aggregates, and the lack of sensitive markers of each oligomeric species.40 Screening assays based on thioflavin-S fluorescence or Congo-red absorbance have been used to identify inhibitors of aggregation of synthetic Af peptide. The reported compounds suffer from relatively low potency (effective at <10 pM) and "flat" SARs." 43... 

The oxazolidinone-based compounds are the most common (Figure 23.1), and examples include antibacterial,27-28 adhesion receptor antagonists,29-30 tumor necrosis factor inhibitors,31 platelet aggregation inhibitors,32 antimigraine drugs,33 and monoamine oxidase inhibitors.3435 In one case, an oxazolidinone has been used as a transdermal drug delivery agent.36... 

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