［1］Shuker SB,Hajduk PJ,Meadows RP,et al.Discovering high-affinity ligands for proteins:SAR by NMR[J].Science,1996,274(5292):1531-1536. ［2］Gargaro AR,Soteriou A,Frenkiel TA,et al.The solution structure of the complex of Lactobacillus casei dihydrofolate reductase with methotrexate[J].J Mol Biol,1998,277(1):119-134. ［3］Wlodawer A,Vondrasek J.Inhibitors of HIV-1 protease:a major success of structre-assisted drug design[J].Annu Rev Biophys Biomol Struct,1998,27:249-284. ［4］Stockmana BJ,Dalvit C.NMR screening techniques in drug discovery and drug design[J].Progress in Nuclear Magnetic Resonance Spectroscopy,2002,41:187-231. ［5］Bjerring M,Vosegaard T,Malmendal A,et al.Methodological development of solid-state NMR for characterization of membrane proteins[J].Concepts in Magnetic Resonance Part A,2003,18A(2):111-129. ［6］Bak M,Schultz R,Nielsen NC.Numerical simulations for experiment design and extraction of structural parameters in biological solid-state NMR spectroscopy.In:Kiihne SR,de Groot HJM,eds.Perspectives on Solid-State NMR in Biology.Dordrecht.Holland:Kluwer Academic Publishers,2001.95-109. ［7］Pochapsky SS,Pochapsky TC.Nuclear magnetic resonance as a tool in drug discovery,metabolism and disposition[J].Current Topics in Medicinal Chemistry,2001,1(5):427-441. ［8］Jardetzky O.Protein dynamics and conformational transitions in allosteric proteins[J].Prog Biophys Mol Biol,1996,65(3):171-218. ［9］Nieto PM,Birdsall B,Morgan WD.Frenkiel TA:correlated bond rotations in interactions of arginine residues with ligand carboxylate groups in protein ligand complexes[J].FEBS Lett,1977,405(1):16-20. ［10］Mark G,Echols N.Exploring the range of protein flexibility,from a structural proteomics perspective[J].Current Opinion in Chemical Biology,2004,8(1):14-19. ［11］Kay LE.Correlation between binding and dynamics at SH2 domain interfaces[J].Nat Struct Boil,1998,5:156-163. ［12］Ben Davis1,Mohammad Afshar1,Gabriele Varani.Rational design of inhibitors of HIV-1 TAR RNA through the stabilisation of electrostatic "hot spots"[J].J Mol Biol,2004,336(2):343-356. ［13］Gordon CK,Roberts.Applications of NMR in drug discovery[J].DDT,2000,5(6):230-240. ［14］Murray Coles,Heller M,Kessler H.NMR-based screening technologies[J].DDT,2003,8(17):803-810. ［15］Christopher A.Lepre,library design for NMR-based screening[J].DDT,2001,6(3):133-140. ［16］Maria van Dongen,Weigelt J.Structure-based screening and design in drug discovery[J].DDT,2002,7(8):471-478.
The Application of NMR Prediction Algorithms to Developing Screening Sets for SAR by NMR
Abstract
SAR by NMR is fast becoming a general approach to identifying possible hits by utilizing NMR experimentation to monitor the binding of a small molecule to a protein. The general approach is to mix together a soup containing a target protein used for screening and a number of possible active pharmaceutical agents. Those moieties which bind to the protein have different diffusion dynamics and the resulting NMR spectra will exhibit the absence of resonances for the complexed molecules. The odious task of identifying the complexing molecule(s) generally requires visual interrogation. The comparison of the spectra of the individual mixture components are compared with the spectrum of the mixture after diffusion editing. This comparison process will allow the identification of those resonances in the individual materials which have been nulled in the mixture spectrum, thereby allowing identification of the binding species. With the intention to perform measurements on many mixtures in an automated fashion, once again the challenge is no longer the data acquisition. Experimental design is crucial to ensure that there is minimum overlap between the spectra for each of the mixture components. We will describe how NMR prediction algorithms can be used to optimize the experimental design process and introduce visualization tools which can dramatically aid the analysis process.
我的社区
签到
【七月征文】不一YOUNG实验“猿”
报名开启：ICS2024第十三届光谱网络会议！
巡检超百家 丹纳赫集团参与第四届客户关怀季
推荐收藏！盘点中药材及饮片检测解决方案
