NMR screening in drug discovery Moore 57 target size; our in-house drug targets are mostly very large signals via line broadening, transferred NOEs, or diffusion by nmr standards. The NMR screening methods we cur- based methods, appear to be better suited for screening of rently employ, however, differ from the sar by NMr larger targets. It is probable that hybrid approaches com method both in implementation and philosophy. Our bining the two types of methods will be of utility in some method, the SHAPES strategy, uses standard iD line drug design programs. Although many groups are known to broadening and 2D transferred NOE measurements to be working in the field, the literature describing these detect binding of a limited ( 200)but diverse library of methods is very thin. It is probable that some pharmaceuti low molecular weight, soluble scaffolds to a potential drug cal firms will prefer to retain their methods as trade secrets target. These scaffolds are derived largely from shapes, or or wait to patent their methods before publication frameworks, most commonly found in known therapeutic Hopefully, as methods evolve more groups will be willing agents 123) and as such represent approximations tosuc- and able to publish their findings. For now, however, in the cessful regions of diversity space enduring battle between industrial scientists and their legal Following screening, weak binding( Kd-HM-mM)scaf departments, the lawyers appear to be winni folds. most of which would be missed in a standard Acknowledgements synthesis of combinatorial libraries, and bias the first com- contributions to the SHAPES project. pounds that undergo enzyme-directed high-throughput References and recommended reaa\,of Papers of particular interest, published within the annual perio drug targets indicate that HTs hit rates for compounds have been highlighted as selected based on NMR SHAPES hits may be higher by of special interes fourfold or more than in a control set of randomly selected es of outstanding interest compounds(CA Lepre, J Fejzo, Jw Peng, JM Moore, 1. Campbell ID, Dwek RA: Biological Spectroscopy. Menlo Park unpublished data). Data from SHAPES hits may also be used advantageously in computational efforts, such as virtual 2. Dwek RA: Nuclear Magnetic Resonance in Biochemistry. Oxford screening, where databases of molecules, either real or virtu cred accordin their synthetic ac 3. James TL: Nuclear Magnetic Resonance in Biochemistry. New York: shape, flexibility, strain energy, similarity to known leads, pharmacophores, docking scores, or other properties relevant 4, NiF: Recent developments in transferred NOE methods, Prog vity, such as lipophilicity or metabolic stability complete description of the SHAPES strategy 5. Shuker SB, Hajduk PJ, Meadows RP, Fesik SW: Discovering and in drug design will be presented elsewhere high-affinity ligands for proteins: SAR by NMR. Science 1996 274:1531-1534 SaR by NmR and the shaPes strategy are similar in that Murcko MA: Recent advances in ligand design methods. In they are both protocols for drug design using NMR, rather Boyd DB. New York: Wiley and Sons: 1997: 1-66 咖如时m如bR22,数电mmm10 NMR are in their basic objectives. SaR by NMR is a very 8. Murcko MA: An introduction to de novo ligand design In Practical elegant but resource intensive method of designing very Application of tight binding(nanomolar affinity) inhibitors using NMR as New York: Marcel Dekker, inc: 1997: 305-354 the principal technology. Alternatively, the go I of sh 9. Mattos C, Ringe D: Locating and characterizing binding sites or proteins. Nat Biotechnol 1996. 14: 595-599 creening and the subsequent follow-up experiments is to establish one or more lead classes of micromol g X, Jeffery CJ, Mattos C, Petsko GA An experimental approach to mapping th compounds that may be further optimized using more effi crystalline proteins. J Phys nt, high-throughput methods, such as HTS and 1. Liepinsh E, Otting G: Organic solvents identify specific ligand combinatorial chemistry. We believe the latter methods may. binding sites on protein surfaces. Nat Biotechnol 1997,15: 264-268 be better suited for exploring the larger regions of chemical An NMR study to examine the binding of solvent molecules to lysozyme Ity space necessary to maximIze in otro potency. Conclusion eakly to sites formed due to crystal packing NMR methods detect NMR screening methods show promise as a highly useful occupancy problems of MSCS path to drug discovery. Although the NMR methods used 12. Hajduk P). Sheppard G, Nettesheim DG, Olejniczak ET, Shuker SB. screening are not novel, application of these methods for HTS of compound libraries forms the basis for several 1195818-582 unique approaches to ligand design. SAR by NMR, despite Application of the SAR by NMR method to design two potent (<25 nM) its limitations, appears to be the method of choice for drug inhibitors of stromelysin. This work provides a step by targets <30 kDa. Other approaches that monitor the ligand ing directly in the field