Discovery of potent nonpeptide inhibitors of stromelysin using SAR by NMR

AUTHORS

Hadjuk PJ , Sheppard G , Nettesheim D , Olejniczak ET , Shuker SB , Meadows RP , Steinman DH , Carrera GM , Marcotte PA , Severin J , Walter K , Smith H , Gubbins E , Simmer R , Holzman TF , Morgan DW , Davidsen SK , Summers JB , Fesik SW . Journal of the American Chemical Society. 1997 6 25; 25(119). 5818-5827

ABSTRACT

With the use of an NMR-based method, potent (IC₅₀ < 25 nM) nonpeptide inhibitors of the matrix metalloproteinase stromelysin (MMP-3) were discovered. The method, called SAR by NMR (for structure−activity relationships by nuclear magnetic resonance), involves the identification, optimization, and linking of compounds that bind to proximal sites on a protein. Using this technique, two ligands that bind weakly to stromelysin (acetohydroxamic acid, K_D = 17 mM; 3-(cyanomethyl)-4‘-hydroxybiphenyl, K_D = 0.02 mM) were identified. On the basis of NMR-derived structural information, the two fragments were connected to produce a 15 nM inhibitor of this enzyme. This compound was rapidly discovered (less than 6 months) and required only a minimal amount of chemical synthesis. These studies indicate that the SAR by NMR method can be effectively applied to enzymes to yield potent lead inhibitorsan important part of the drug discovery process.