Skip to main content

Advertisement

SpringerLink
Log in

The role of NMR in leveraging dynamics and entropy in drug design

  • Perspective
  • Published:
Journal of Biomolecular NMR Aims and scope Submit manuscript

A Correction to this article was published on 20 September 2020

This article has been updated

Abstract

Nuclear magnetic resonance (NMR) spectroscopy has contributed to structure-based drug development (SBDD) in a unique way compared to the other biophysical methods. The potency of a ligand binding to a protein is dictated by the binding free energy, which is an intricate interplay between entropy and enthalpy. In addition to providing the atomic resolution structural information, NMR can help to identify protein–ligand interactions that potentially contribute to the enthalpic component of the free energy. NMR can also illuminate dynamic aspects of the interaction, which correspond to the entropic term of the free energy. The ability of NMR to access both terms in the free energy equation stems from the suite of experiments developed to shed light on various aspects that contribute to both entropy and enthalpy, deepening our understanding of the biological function of macromolecules and assisting to target them in physiological conditions. Here we provide a brief account of the contribution of NMR to SBDD, highlighting hallmark examples and discussing the challenges that demand further method development. In the era of integrated biology, the unique ability of NMR to directly ascertain structural and dynamical aspects of macromolecule and monitor changes in these properties upon engaging a ligand can be combined with computational and other structural and biophysical methods to provide a more complete picture of the energetics of drug engagement with the target. Such efforts can be used to engineer better drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Change history

  • 20 September 2020

    Unfortunately, in the original publication, Fig. 5 was published incorrectly. The correct version is given below:

References

  • Agafonov RV, Wilson C, Otten R, Buosi V, Kern D (2014) Energetic dissection of Gleevec's selectivity toward human tyrosine kinases. Nat Struct Mol Biol 21:848–853

    Google Scholar 

  • Ahlbach CL et al (2015) Beyond cyclosporine A: conformation-dependent passive membrane permeabilities of cyclic peptide natural products. Future Med Chem 7:2121–2130

    Google Scholar 

  • Akke M (2012) Conformational dynamics and thermodynamics of protein-ligand binding studied by NMR relaxation. Biochem Soc Trans 40:419–423

    Google Scholar 

  • Akke M, Brueschweiler R, Palmer AG (1993) NMR order parameters and free energy: an analytical approach and its application to cooperative calcium(2+) binding by calbindin D9k. J Am Chem Soc 115:9832–9833

    Google Scholar 

  • Alberty RA, Hammes GG (1958) Application of the theory of diffusion-controlled reactions to enzyme kinetics. J Phys Chem 62:154–159

    Google Scholar 

  • Albrand JP, Birdsall B, Feeney J, Roberts GCK, Burgen ASV (1979) The use of transferred nuclear Overhauser effects in the study of the conformations of small molecules bound to proteins. Int J Biol Macromol 1:37–41

    Google Scholar 

  • Aldeghi M, Gapsys V, de Groot BL (2018) Accurate estimation of ligand binding affinity changes upon protein mutation. ACS Cent Sci 4:1708–1718

    Google Scholar 

  • Ambadipudi S, Reddy JG, Biernat J, Mandelkow E, Zweckstetter M (2019) Residue-specific identification of phase separation hot spots of Alzheimer's-related protein tau. Chem Sci 10:6503–6507

    Google Scholar 

  • Anthis NJ, Clore GM (2015) Visualizing transient dark states by NMR spectroscopy. Q Rev Biophys 48:35–116

    Google Scholar 

  • Appavoo SD, Huh S, Diaz DB, Yudin AK (2019) Conformational control of macrocycles by remote structural modification. Chem Rev 119:9724–9752

    Google Scholar 

  • Balaram P, Bothner-By AA, Dadok J (1972) Negative nuclear Overhuaser effects as probes of macromolecular structure. J Am Chem Soc 94:4015–4017

    Google Scholar 

  • Balazs AYS et al (2019) Free ligand 1D NMR conformational signatures to enhance structure based drug design of a Mcl-1 inhibitor (AZD5991) and other synthetic macrocycles. J Med Chem 62:9418–9437

    Google Scholar 

  • Ban D, Iconaru LI, Ramanathan A, Zuo J, Kriwacki RW (2017) A small molecule causes a population shift in the conformational landscape of an intrinsically disordered protein. J Am Chem Soc 139:13692–13700

    Google Scholar 

  • Berlow RB, Dyson HJ, Wright PE (2017) Hypersensitive termination of the hypoxic response by a disordered protein switch. Nature 543:447

    ADS  Google Scholar 

  • Bom A, Hope F, Rutherford S, Thomson K (2009) Preclinical pharmacology of sugammadex. J Crit Care 24:29–35

    Google Scholar 

  • Bonomi M, Pellarin R, Vendruscolo M (2018) Simultaneous determination of protein structure and dynamics using cryo-electron microscopy. Biophys J 114:1604–1613

    Google Scholar 

  • Bowman GR, Geissler PL (2012) Equilibrium fluctuations of a single folded protein reveal a multitude of potential cryptic allosteric sites. Proc Natl Acad Sci 109:11681

    ADS  Google Scholar 

  • Bowman GR, Bolin ER, Hart KM, Maguire BC, Marqusee S (2015) Discovery of multiple hidden allosteric sites by combining Markov state models and experiments. Proc Natl Acad Sci 112:2734

    ADS  Google Scholar 

  • Bradshaw JM et al (2015) Prolonged and tunable residence time using reversible covalent kinase inhibitors. Nat Chem Biol 11:525–531

    Google Scholar 

  • Carneiro MG, Ab E, Theisgen S, Siegal G (2017) NMR in structure-based drug design. Essays Biochem 61:485–493

    Google Scholar 

  • Caro JA et al (2017) Entropy in molecular recognition by proteins. Proc Natl Acad Sci USA 114:6563–6568

    Google Scholar 

  • Carroll MJ et al (2012) Evidence for dynamics in proteins as a mechanism for ligand dissociation. Nat Chem Biol 8:246–252

    Google Scholar 

  • Chang CE, Chen W, Gilson MK (2007) Ligand configurational entropy and protein binding. Proc Natl Acad Sci USA 104:1534–1539

    ADS  Google Scholar 

  • Chodera JD, Mobley DL (2013) Entropy-enthalpy compensation: role and ramifications in biomolecular ligand recognition and design. Annu Rev Biophys 42:121–142

    Google Scholar 

  • Chung BKW, White CJ, Scully CCG, Yudin AK (2016) The reactivity and conformational control of cyclic tetrapeptides derived from aziridine-containing amino acids. Chem Sci 7:6662–6668

    Google Scholar 

  • Cicero DO, Barbato G, Bazzo R (1995) NMR analysis of molecular flexibility in solution: a new method for the study of complex distributions of rapidly exchanging conformations. Application to a 13-residue peptide with an 8-residue loop. J Am Chem Soc 117:1027–1033

    Google Scholar 

  • Copeland RA, Pompliano DL, Meek TD (2006) Drug–target residence time and its implications for lead optimization. Nat Rev Drug Discov 5:730–739

    Google Scholar 

  • Dalvit C et al (2000) Identification of compounds with binding affinity to proteins via magnetization transfer from bulk water. J Biomol NMR 18:65–68

    Google Scholar 

  • Dalvit C, Ardini E, Fogliatto GP, Mongelli N, Veronesi M (2004) Reliable high-throughput functional screening with 3-FABS. Drug Discov Today 9:595–602

    Google Scholar 

  • Das K, Arnold E (2013a) HIV-1 reverse transcriptase and antiviral drug resistance. Part 1. Curr Opin Virol 3:111–118

    Google Scholar 

  • Das K, Arnold E (2013b) HIV-1 reverse transcriptase and antiviral drug resistance Part 2. Curr Opin Virol 3:119

    Google Scholar 

  • Dautzenberg FM, Neysari S (2005) Irreversible binding kinetics of neuropeptide Y ligands to Y2 but not to Y1 and Y5 receptors. Pharmacology 75:21–29

    Google Scholar 

  • Diehl C et al (2010) Protein flexibility and conformational entropy in ligand design targeting the carbohydrate recognition domain of galectin-3. J Am Chem Soc 132:14577–14589

    Google Scholar 

  • Dill KA, Bromberg S (2011) Molecular driving forces : statistical thermodynamics in biology, chemistry, physics, and nanoscience. Garland Science, New York

    Google Scholar 

  • Disse B, Speck GA, Rominger KL, Witek TJ Jr, Hammer R (1999) Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life Sci 64:457–464

    Google Scholar 

  • Dunitz JD (1994) The entropic cost of bound water in crystals and biomolecules. Science 264:670

    ADS  Google Scholar 

  • Elg M, Gustafsson D, Deinum J (1997) The importance of enzyme inhibition kinetics for the effect of thrombin inhibitors in a rat model of arterial thrombosis. Thromb Haemost 78:1286–1292

    Google Scholar 

  • Fang Z et al (2018) Inhibition of K-RAS4B by a unique mechanism of action: stabilizing membrane-dependent occlusion of the effector-binding site. Cell Chem Biol 25:1327–1336.e4

    Google Scholar 

  • Fawzi NL, Ying J, Ghirlando R, Torchia DA, Clore GM (2011) Atomic-resolution dynamics on the surface of amyloid-beta protofibrils probed by solution NMR. Nature 480:268–272

    ADS  Google Scholar 

  • Fawzi NL, Ying J, Torchia DA, Clore GM (2012) Probing exchange kinetics and atomic resolution dynamics in high-molecular-weight complexes using dark-state exchange saturation transfer NMR spectroscopy. Nat Protoc 7:1523–1533

    Google Scholar 

  • Fedorov DG, Kitaura K (2009) The fragment molecular orbital method : practical applications to large molecular systems. CRC Press, Boca Raton

    Google Scholar 

  • Fedorov DG, Nagata T, Kitaura K (2012) Exploring chemistry with the fragment molecular orbital method. Phys Chem Chem Phys 14:7562–7577

    Google Scholar 

  • Fernandez A, Fraser C, Scott LR (2012) Purposely engineered drug-target mismatches for entropy-based drug optimization. Trends Biotechnol 30:1–7

    Google Scholar 

  • Ferrari AM, Degliesposti G, Sgobba M, Rastelli G (2007) Validation of an automated procedure for the prediction of relative free energies of binding on a set of aldose reductase inhibitors. Bioorg Med Chem 15:7865–7877

    Google Scholar 

  • Ferreira de Freitas R, Schapira M (2017) A systematic analysis of atomic protein-ligand interactions in the PDB. Medchemcomm 8:1970–1981

    Google Scholar 

  • Fersht AR et al (1984) Analysis of enzyme structure and activity by protein engineering. Angew Chem Int Ed Engl 23:467–473

    Google Scholar 

  • Fersht AR et al (1985) Hydrogen bonding and biological specificity analysed by protein engineering. Nature 314:235–238

    ADS  Google Scholar 

  • Fox JM, Zhao M, Fink MJ, Kang K, Whitesides GM (2018) The molecular origin of enthalpy/entropy compensation in biomolecular recognition. Annu Rev Biophys 47:223–250

    Google Scholar 

  • Frederick KK, Marlow MS, Valentine KG, Wand AJ (2007) Conformational entropy in molecular recognition by proteins. Nature 448:325–329

    ADS  Google Scholar 

  • Freire E (2008) Do enthalpy and entropy distinguish first in class from best in class? Drug Discov Today 13:869–874

    Google Scholar 

  • Freire E (2009) A thermodynamic approach to the affinity optimization of drug candidates. Chem Biol Drug Des 74:468–472

    Google Scholar 

  • Furuya T, Kamlet AS, Ritter T (2011) Catalysis for fluorination and trifluoromethylation. Nature 473:470–477

    ADS  Google Scholar 

  • Gabrielsson J et al (2009) Early integration of pharmacokinetic and dynamic reasoning is essential for optimal development of lead compounds: strategic considerations. Drug Discov Today 14:358–372

    Google Scholar 

  • Geist L et al (2017) Direct NMR probing of hydration shells of protein ligand interfaces and its application to drug design. J Med Chem 60:8708–8715

    Google Scholar 

  • Gil S, Espinosa JF, Parella T (2010) IPAP–HSQMBC: measurement of long-range heteronuclear coupling constants from spin-state selective multiplets. J Magn Reson 207:312–321

    ADS  Google Scholar 

  • Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA (2015) Applications of fluorine in medicinal chemistry. J Med Chem 58:8315–8359

    Google Scholar 

  • Gilson MK et al (2016) BindingDB in 2015: a public database for medicinal chemistry, computational chemistry and systems pharmacology. Nucleic Acids Res 44:D1045–D1053

    Google Scholar 

  • Goldbach L et al (2019) Folding then binding vs folding through binding in macrocyclic peptide inhibitors of human pancreatic alpha-amylase. ACS Chem Biol 14:1751–1759

    Google Scholar 

  • Gorgulla C et al (2020) An open-source drug discovery platform enables ultra-large virtual screens. Nature 580:663–668

    ADS  Google Scholar 

  • Holloway MK et al (1995) A priori prediction of activity for HIV-1 protease inhibitors employing energy minimization in the active site. J Med Chem 38:305–317

    Google Scholar 

  • Horne WS, Olsen CA, Beierle JM, Montero A, Ghadiri MR (2009) Probing the bioactive conformation of an archetypal natural product HDAC inhibitor with conformationally homogeneous triazole-modified cyclic tetrapeptides. Angew Chem Int Ed 48:4718–4724

    Google Scholar 

  • Igumenova TI, Frederick KK, Wand AJ (2006) Characterization of the fast dynamics of protein amino acid side chains using NMR relaxation in solution. Chem Rev 106:1672–1699

    Google Scholar 

  • Jain AN et al (2019) Complex macrocycle exploration: parallel, heuristic, and constraint-based conformer generation using ForceGen. J Comput Aided Mol Des 33:531–558

    ADS  Google Scholar 

  • Janin J (1995) Protein-protein recognition. Prog Biophys Mol Biol 64:145–166

    Google Scholar 

  • Jencks WP (1975) Binding energy, specificity, and enzymic catalysis: the circe effect. Adv Enzymol Relat Areas Mol Biol 43:219–410

    Google Scholar 

  • Jorge C, Marques BS, Valentine KG, Wand AJ (2019) Characterizing protein hydration dynamics using solution NMR spectroscopy. In: Wand AJ (ed) Methods in enzymology, vol 615. Academic Press, Cambridge, pp 77–101

    Google Scholar 

  • Joshi P, Vendruscolo M (2015) Druggability of intrinsically disordered proteins. Adv Exp Med Biol 870:383–400

    Google Scholar 

  • Kasinath V, Sharp KA, Wand AJ (2013) Microscopic insights into the NMR relaxation-based protein conformational entropy meter. J Am Chem Soc 135:15092–15100

    Google Scholar 

  • Kauzmann W (1959) Some factors in the interpretation of protein denaturation. Adv Protein Chem 14:1–63

    Google Scholar 

  • Kawasaki Y, Freire E (2011) Finding a better path to drug selectivity. Drug Discov Today 16:985–990

    Google Scholar 

  • Kay LE, Prestegard JH (1987a) Methyl group dynamics from relaxation of double quantum filtered NMR signals. Application to deoxycholate. J Am Chem Soc 109:3829–3835

    Google Scholar 

  • Kay LE, Prestegard JH (1987b) Methyl group dynamics from relaxation of double quantum filtered NMR signals. Application to deoxycholate. J Am Chem Soc 109:3829–3835

    Google Scholar 

  • Keighley W (2011) The need for high throughput kinetics early in the drug discovery process. Drug Discov World Summer 12:39–45

    Google Scholar 

  • Kitaura K, Ikeo E, Asada T, Nakano T, Uebayasi M (1999) Fragment molecular orbital method: an approximate computational method for large molecules. Chem Phys Lett 313:701–706

    ADS  Google Scholar 

  • Kleckner IR, Foster MP (2011) An introduction to NMR-based approaches for measuring protein dynamics. Biochim Biophys Acta 1814:942–968

    Google Scholar 

  • Klotz IM (1959) Protein behavior. Science 129:608

    ADS  Google Scholar 

  • Kostylev MA et al (2018) Liquid and hydrogel phases of PrP(C) linked to conformation shifts and triggered by Alzheimer's amyloid-beta oligomers. Mol Cell 72:426–443.e12

    Google Scholar 

  • Kövér KE, Forgó P (2004) J-modulated ADEQUATE (JM-ADEQUATE) experiment for accurate measurement of carbon–carbon coupling constants. J Magn Reson 166:47–52

    ADS  Google Scholar 

  • Kovermann M, Rogne P, Wolf-Watz M (2016) Protein dynamics and function from solution state NMR spectroscopy. Q Rev Biophys 49:e6

    Google Scholar 

  • Kranz M et al (2006) Solution, solid phase and computational structures of apicidin and its backbone-reduced analogs. J Pept Sci 12:383–388

    Google Scholar 

  • Krishnamurthy VV (1996) Excitation-sculptured indirect-detection experiment (EXSIDE) for long-range CH coupling-constant measurement. J Magn Reson Ser A 121:33–41

    ADS  Google Scholar 

  • Lee C-J et al (2016) Drug design from the cryptic inhibitor envelope. Nat Commun 7:10638

    ADS  Google Scholar 

  • Lee AL, Kinnear SA, Wand AJ (2000) Redistribution and loss of side chain entropy upon formation of a calmodulin-peptide complex. Nat Struct Biol 7:72–77

    Google Scholar 

  • Liu Y et al (2017) Unequivocal determination of complex molecular structures using anisotropic NMR measurements. Science 356:eaam5349

    Google Scholar 

  • Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK (2007) BindingDB: a web-accessible database of experimentally determined protein–ligand binding affinities. Nucleic Acids Res 35:D198–D201

    Google Scholar 

  • Luchinat E et al (2020) Drug screening in human cells by nmr spectroscopy allows the early assessment of drug potency. Angew Chem Int Ed Engl 59:6535–6539

    Google Scholar 

  • Luckner SR, Liu N, Am Ende CW, Tonge PJ, Kisker C (2010) A slow, tight binding inhibitor of InhA, the enoyl-acyl carrier protein reductase from Mycobacterium tuberculosis. J Biol Chem 285:14330–14337

    Google Scholar 

  • Luque I, Freire E (2002) Structural parameterization of the binding enthalpy of small ligands. Proteins: Struct Funct Bioinform 49:181–190

    Google Scholar 

  • Malde AK, Hill TA, Iyer A, Fairlie DP (2019) Crystal structures of protein-bound cyclic peptides. Chem Rev 119:9861–9914

    Google Scholar 

  • Manglik A et al (2015) Structural insights into the dynamic process of β2-adrenergic receptor signaling. Cell 161:1101–1111

    Google Scholar 

  • Markovitch O, Agmon N (2007) Structure and energetics of the hydronium hydration shells. J Phys Chem A 111:2253–2256

    Google Scholar 

  • Marlow MS, Dogan J, Frederick KK, Valentine KG, Wand AJ (2010) The role of conformational entropy in molecular recognition by calmodulin. Nat Chem Biol 6:352–358

    Google Scholar 

  • Mauldin RV, Carroll MJ, Lee AL (2009) Dynamic dysfunction in dihydrofolate reductase results from antifolate drug binding: modulation of dynamics within a structural state. Structure 17:386–394

    Google Scholar 

  • Merino F, Raunser S (2017) Electron cryo-microscopy as a tool for structure-based drug development. Angew Chem Int Ed Engl 56:2846–2860

    Google Scholar 

  • Milo R, Phillips RB, Orme N, Garland S (2016) Cell biology by the numbers. Garland Science, Taylor & Francis Group, New York, Abingdon

    Google Scholar 

  • Mizukoshi Y et al (2016a) Improvement of ligand affinity and thermodynamic properties by NMR-based evaluation of local dynamics and surface complementarity in the receptor-bound state. Angew Chem Int Ed Engl 55:14606–14609

    Google Scholar 

  • Mizukoshi Y et al (2016b) Improvement of ligand affinity and thermodynamic properties by NMR-based evaluation of local dynamics and surface complementarity in the receptor-bound state. Angew Chem Int Ed 55:14606–14609

    Google Scholar 

  • Morrison C (2018) Constrained peptides' time to shine? Nat Rev Drug Discov 17:531–533

    Google Scholar 

  • Namanja AT et al (2010) Toward flexibility-activity relationships by NMR spectroscopy: dynamics of Pin1 ligands. J Am Chem Soc 132:5607–5609

    Google Scholar 

  • Ndukwe IE et al (2019) 13C NMR-based approaches for solving challenging stereochemical problems. Org Lett 21:4072–4076

    Google Scholar 

  • Nguyen QNN, Schwochert J, Tantillo DJ, Lokey RS (2018) Using (1)H and (13)C NMR chemical shifts to determine cyclic peptide conformations: a combined molecular dynamics and quantum mechanics approach. Phys Chem Chem Phys 20:14003–14012

    Google Scholar 

  • Nikiforovich GV, Kövér KE, Zhang W-J, Marshall GR (2000) Cyclopentapeptides as flexible conformational templates. J Am Chem Soc 122:3262–3273

    Google Scholar 

  • Nitsche C, Otting G (2017) Pseudocontact shifts in biomolecular NMR using paramagnetic metal tags. Prog Nucl Magn Reson Spectrosc 98–99:20–49

    Google Scholar 

  • Nitsche C, Otting G (2018) NMR studies of ligand binding. Curr Opin Struct Biol 48:16–22

    Google Scholar 

  • Norton SR, Leung WE, Chandrashekaran RI, MacRaild AC (2016) Applications of 19F-NMR in fragment-based drug Discovery. Molecules 21:860

    Google Scholar 

  • Nucci NV, Pometun MS, Wand AJ (2011) Site-resolved measurement of water-protein interactions by solution NMR. Nat Struct Mol Biol 18:245–249

    Google Scholar 

  • Ono S et al (2019) Conformation and permeability: cyclic hexapeptide diastereomers. J Chem Inf Model 59:2952–2963

    Google Scholar 

  • Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM (2013) K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503:548

    ADS  Google Scholar 

  • Otero-Ramirez ME, Passioura T, Suga H (2018) Structural features and binding modes of thioether-cyclized peptide ligands. Biomedicines 6:116

    Google Scholar 

  • Otting G, Liepinsh E (1995) Protein hydration viewed by high-resolution NMR spectroscopy: implications for magnetic resonance image contrast. Acc Chem Res 28:171–177

    Google Scholar 

  • Otting G, Wuethrich K (1989) Studies of protein hydration in aqueous solution by direct NMR observation of individual protein-bound water molecules. J Am Chem Soc 111:1871–1875

    Google Scholar 

  • Oxenoid K, Chou JJ (2016) A functional NMR for membrane proteins: dynamics, ligand binding, and allosteric modulation. Protein Sci 25:959–973

    Google Scholar 

  • Öztürk H, Özgür A, Ozkirimli E (2018) DeepDTA: deep drug–target binding affinity prediction. Bioinformatics 34:i821–i829

    Google Scholar 

  • Page MI (1991) The energetics of intramolecular reactions and enzyme catalysis. Philos Trans R Soc Lond B 332:149–156

    ADS  Google Scholar 

  • Palmer AG 3rd (2001) NMR probes of molecular dynamics: overview and comparison with other techniques. Annu Rev Biophys Biomol Struct 30:129–155

    Google Scholar 

  • Palmer AG 3rd (2004) NMR characterization of the dynamics of biomacromolecules. Chem Rev 104:3623–3640

    Google Scholar 

  • Pan AC, Borhani DW, Dror RO, Shaw DE (2013) Molecular determinants of drug-receptor binding kinetics. Drug Discov Today 18:667–673

    Google Scholar 

  • Perola E, Charifson PS (2004) Conformational analysis of drug-like molecules bound to proteins: an extensive study of ligand reorganization upon binding. J Med Chem 47:2499–2510

    Google Scholar 

  • Petros AM et al (2010) Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR. Bioorg Med Chem Lett 20:6587–6591

    Google Scholar 

  • Phillips C et al (2011) Design and structure of stapled peptides binding to estrogen receptors. J Am Chem Soc 133:9696–9699

    Google Scholar 

  • Pitsawong W et al (2018) Dynamics of human protein kinase Aurora A linked to drug selectivity. eLife 7:e36656

    Google Scholar 

  • Prosser RS, Kim TH (2015) Nuts and bolts of CF3 and CH3 NMR toward the understanding of conformational exchange of GPCRs. In: Filizola M (ed) G protein-coupled receptors in drug discovery: methods and protocols. Springer, New York, pp 39–51

    Google Scholar 

  • Punjani A, Fleet DJ (2020) 3D variability analysis: directly resolving continuous flexibility and discrete heterogeneity from single particle cryo-EM images. bioRxiv. https://doi.org/10.1101/2020.04.08.032466

    Article  Google Scholar 

  • Reibarkh M, Malia TJ, Wagner G (2006a) NMR distinction of single- and multiple-mode binding of small-molecule protein ligands. J Am Chem Soc 128:2160–2161

    Google Scholar 

  • Reibarkh M, Malia TJ, Hopkins BT, Wagner G (2006b) Identification of individual protein-ligand NOEs in the limit of intermediate exchange. J Biomol NMR 36:1–11

    Google Scholar 

  • Reibarkh M, Williamson RT, Martin GE, Bermel W (2013) Broadband inversion of 1JCC responses in 1, n-ADEQUATE spectra. J Magn Reson 236:126–133

    ADS  Google Scholar 

  • Reif B et al (1996) ADEQUATE, a new set of experiments to determine the constitution of small molecules at natural abundance. J Magn Reson 118:282–285

    ADS  Google Scholar 

  • Renaud JP et al (2016) Biophysics in drug discovery: impact, challenges and opportunities. Nat Rev Drug Discov 15:679–698

    Google Scholar 

  • Renaud JP et al (2018) Cryo-EM in drug discovery: achievements, limitations and prospects. Nat Rev Drug Discov 17:471–492

    Google Scholar 

  • Reynolds CH, Holloway MK (2011) Thermodynamics of ligand binding and efficiency. ACS Med Chem Lett 2:433–437

    Google Scholar 

  • Robertson IM, Spyracopoulos L, Sykes BD (2009) The evaluation of isotope editing and filtering for protein—ligand interaction elucidation by NMR. In: Puglisi JD (ed) Biophysics and the challenges of emerging threats. Springer, Dordrecht, pp 101–119

    Google Scholar 

  • Saleh T, Rossi P, Kalodimos CG (2017) Atomic view of the energy landscape in the allosteric regulation of Abl kinase. Nat Struct Mol Biol 24:893–901

    Google Scholar 

  • Saur M et al (2020) Fragment-based drug discovery using cryo-EM. Drug Discov Today 25:485–490

    Google Scholar 

  • Saurí J, Parella T, Espinosa JF (2013) CLIP-HSQMBC: easy measurement of small proton–carbon coupling constants in organic molecules. Org Biomol Chem 11:4473–4478

    Google Scholar 

  • Saurí J, Parella T, Williamson RT, Martin GE (2017) Improving the performance of J-modulated ADEQUATE experiments through homonuclear decoupling and non-uniform sampling. Magn Reson Chem 55:191–197

    Google Scholar 

  • Scapin G, Potter CS, Carragher B (2018) Cryo-EM for small molecules discovery, design, understanding, and application. Cell Chem Biol 25:1318–1325

    Google Scholar 

  • Schreiber SL, Crabtree GR (1992) The mechanism of action of cyclosporin A and FK506. Immunol Today 13:136–142

    Google Scholar 

  • Sekhar A, Kay LE (2019) An NMR view of protein dynamics in health and disease. Annu Rev Biophys 48:297–319

    Google Scholar 

  • Sharp KA, Nicholls A, Friedman R, Honig B (1991) Extracting hydrophobic free energies from experimental data: relationship to protein folding and theoretical models [published erratum appears in Biochemistry 1993 May 25;32(20):5490]. Biochemistry 30:9686–9697

  • Shimada I, Ueda T, Kofuku Y, Eddy MT, Wüthrich K (2019) GPCR drug discovery: integrating solution NMR data with crystal and cryo-EM structures. Nat Rev Drug Discov 18:59–82

    Google Scholar 

  • Snyder PW et al (2011) Mechanism of the hydrophobic effect in the biomolecular recognition of arylsulfonamides by carbonic anhydrase. Proc Natl Acad Sci USA 108:17889–17894

    ADS  Google Scholar 

  • Souers AJ et al (2013) ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 19:202–208

    Google Scholar 

  • Stillinger FH (1973) Structure in aqueous solutions of nonpolar solutes from the standpoint of scaled-particle theory. J Solut Chem 2:141–158

    Google Scholar 

  • Stoffel S, Zhang QW, Li DH, Smith BD, Peng JW (2020) NMR relaxation dispersion reveals macrocycle breathing dynamics in a cyclodextrin-based rotaxane. J Am Chem Soc 142:7413–7424

    Google Scholar 

  • Sun H, Kay LE, Tugarinov V (2011) An optimized relaxation-based coherence transfer NMR experiment for the measurement of side-chain order in methyl-protonated, highly deuterated proteins. J Phys Chem B 115:14878–14884

    Google Scholar 

  • Takeuchi K, Wagner G (2006) NMR studies of protein interactions. Curr Opin Struct Biol 16:109–117

    Google Scholar 

  • Takeuchi K, Tokunaga Y, Imai M, Takahashi H, Shimada I (2014) Dynamic multidrug recognition by multidrug transcriptional repressor LmrR. Sci Rep 4:1–12

    Google Scholar 

  • Thafar M, Raies AB, Albaradei S, Essack M, Bajic VB (2019) Comparison study of computational prediction tools for drug-target binding affinities. Front Chem 7:782

    ADS  Google Scholar 

  • Tjandra N, Bax A (1997) Direct measurement of distances and angles in biomolecules by NMR in a dilute liquid crystalline medium. Science 278:1111–1114

    ADS  Google Scholar 

  • Tokunaga Y, Takeuchi K, Takahashi H, Shimada I (2014) Allosteric enhancement of MAP kinase p38α's activity and substrate selectivity by docking interactions. Nat Struct Mol Biol 21:704–711

    Google Scholar 

  • Tokunaga Y, Takeuchi K, Shimada I (2017) Forbidden coherence transfer of 19F nuclei to quantitatively measure the dynamics of a CF3-containing ligand in receptor-bound states. Molecules 22:1492

    Google Scholar 

  • Tokunaga Y, Viennet T, Arthanari H, Takeuchi K (2020) Spotlight on the ballet of proteins: the structural dynamic properties of proteins illuminated by solution NMR. Int J Mol Sci 21:1829

    Google Scholar 

  • Tompa P, Fuxreiter M (2008) Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions. Trends Biochem Sci 33:2–8

    Google Scholar 

  • Tonge PJ (2018) Drug-target kinetics in drug discovery. ACS Chem Neurosci 9:29–39

    Google Scholar 

  • Trigo-Mourino P, Griesinger C, Lee D (2017) Label-free NMR-based dissociation kinetics determination. J Biomol NMR 69:229–235

    Google Scholar 

  • Tugarinov V, Sprangers R, Kay LE (2007) Probing side-chain dynamics in the proteasome by relaxation violated coherence transfer NMR spectroscopy. J Am Chem Soc 129:1743–1750

    Google Scholar 

  • Tzeng SR, Kalodimos CG (2009) Dynamic activation of an allosteric regulatory protein. Nature 462:368–372

    ADS  Google Scholar 

  • Vacic V et al (2012) Disease-associated mutations disrupt functionally important regions of intrinsic protein disorder. PLoS Comput Biol 8:e1002709

    Google Scholar 

  • Vahidi S et al (2020) An allosteric switch regulates Mycobacterium tuberculosis ClpP1P2 protease function as established by cryo-EM and methyl-TROSY NMR. Proc Natl Acad Sci 117:5895

    Google Scholar 

  • Valeur E et al (2017) New modalities for challenging targets in drug discovery. Angew Chem Int Ed Engl 56:10294–10323

    Google Scholar 

  • Vallurupalli P, Bouvignies G, Kay LE (2012) Studying "invisible" excited protein states in slow exchange with a major state conformation. J Am Chem Soc 134:8148–8161

    Google Scholar 

  • Vallurupalli P, Sekhar A, Yuwen T, Kay LE (2017) Probing conformational dynamics in biomolecules via chemical exchange saturation transfer: a primer. J Biomol NMR 67:243–271

    Google Scholar 

  • van der Spoel D, van Maaren PJ, Larsson P, Timneanu N (2006) Thermodynamics of hydrogen bonding in hydrophilic and hydrophobic media. J Phys Chem B 110:4393–4398

    Google Scholar 

  • van Noord JA, Bantje TA, Eland ME, Korducki L, Cornelissen PJ, The Dutch Tiotropium Study Group (2000) A randomised controlled comparison of tiotropium nd ipratropium in the treatment of chronic obstructive pulmonary disease. Thorax 55:289–294

    Google Scholar 

  • Vinogradov AA, Yin Y, Suga H (2019) Macrocyclic peptides as drug candidates: recent progress and remaining Challenges. J Am Chem Soc 141:4167–4181

    Google Scholar 

  • Vulpetti A, Dalvit C (2012) Fluorine local environment: from screening to drug design. Drug Discov Today 17:890–897

    Google Scholar 

  • Wahyudi H, Tantisantisom W, McAlpine SR (2014) Sanguinamide B analogs: identification of active macrocyclic structures. Tetrahedron Lett 55:2389–2393

    Google Scholar 

  • Wand AJ (2001) Dynamic activation of protein function: a view emerging from NMR spectroscopy. Nat Struct Biol 8:926–931

    Google Scholar 

  • Wand AJ (2012) The dark energy of proteins comes to light: conformational entropy and its role in protein function revealed by NMR relaxation. Curr Opin Struct Biol 23:75–81

    Google Scholar 

  • Wand AJ, Sharp KA (2018) Measuring entropy in molecular recognition by proteins. Annu Rev Biophys 47:41–61

    Google Scholar 

  • Wang J et al (2014) Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001–2011). Chem Rev 114:2432–2506

    Google Scholar 

  • Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450:1001–1009

    ADS  Google Scholar 

  • Williams RJ (1981) Studies of larger motions within proteins by nuclear magnetic resonance spectroscopy. Biochem Soc Symp 46:57–72

    ADS  Google Scholar 

  • Wilson JE et al (2016) Discovery of novel indoline cholesterol ester transfer protein inhibitors (CETP) through a structure-guided approach. ACS Med Chem Lett 7:261–265

    Google Scholar 

  • Witek J et al (2016) Kinetic models of cyclosporin A in polar and apolar environments reveal multiple congruent conformational states. J Chem Inf Model 56:1547–1562

    Google Scholar 

  • Witek J et al (2017) Interconversion rates between conformational states as rationale for the membrane permeability of cyclosporines. ChemPhysChem 18:3309–3314

    Google Scholar 

  • Witek J et al (2019) Rationalization of the membrane permeability differences in a series of analogue cyclic decapeptides. J Chem Inf Model 59:294–308

    Google Scholar 

  • Wlodawer A, Vondrasek J (1998) Inhibitors of HIV-1 protease: a major success of structure-assisted drug design. Annu Rev Biophys Biomol Struct 27:249–284

    Google Scholar 

  • Ye L, Van Eps N, Zimmer M, Ernst OP, Scott Prosser R (2016) Activation of the A2A adenosine G-protein-coupled receptor by conformational selection. Nature 533:265

    ADS  Google Scholar 

  • Yip KM, Fischer N, Paknia E, Chari A, Stark H (2020) Breaking the next Cryo-EM resolution barrier—atomic resolution determination of proteins! bioRxiv. https://doi.org/10.1101/2020.05.21.106740

    Article  Google Scholar 

  • Ziarek JJ, Baptista D, Wagner G (2018) Recent developments in solution nuclear magnetic resonance (NMR)-based molecular biology. J Mol Med (Berl) 96:1–8

    Google Scholar 

Download references

Acknowledgements

We thank Dr. Shriya S. Srinivasan for the discussions and critical comments on this manuscript. This work is also supported by JSPS-ISF Joint Research Program and JSPS KAKENHI Grant-in-Aid for Challenging Research (Exploratory) 20H03378 and 20H04722 to KT. HA acknowledges funding from NIH (GM136859) and the Claudia Adams Barr Program for Innovative Cancer Research.

Author information

Author notes

  1. Abhinav Dubey and Koh Takeuchi have contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA

    Abhinav Dubey & Haribabu Arthanari

  2. Cellular and Molecular Biotechnology Research Institute & Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, 135-0064, Japan

    Koh Takeuchi

  3. Analytical Research and Development, Merck & Co., Inc., Rahway, NJ, 07065, USA

    Mikhail Reibarkh

  4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA

    Abhinav Dubey & Haribabu Arthanari

Authors
  1. Abhinav Dubey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Koh Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mikhail Reibarkh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haribabu Arthanari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Koh Takeuchi or Haribabu Arthanari.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dubey, A., Takeuchi, K., Reibarkh, M. et al. The role of NMR in leveraging dynamics and entropy in drug design. J Biomol NMR 74, 479–498 (2020). https://doi.org/10.1007/s10858-020-00335-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10858-020-00335-9

Keywords

Search

Navigation