Abstract
Non-covalent interactions lie at the bases of the molecular recognition process. In medicinal chemistry, understanding how bioactive molecules interact with their target can help to explain structure–activity relationships (SAR) and improve potency of lead compounds. In particular, computational analysis of protein–ligand complexes can help to unravel key interactions and guide structure-based drug design.
The literature describing protein-ligand complexes is typically focused on few types of non-covalent interactions (e.g., hydrophobic contacts, hydrogen bonds, and salt bridges). Stacking interactions involving aromatic rings are also relatively well known to medicinal chemistry practitioners. Potency optimization efforts are often focused on targeting these interactions. However, a variety of underappreciated interactions were shown to have a relevant effect on the stabilization of protein–ligand complexes. This chapter aims at listing selected non-covalent interactions and discuss some examples on how they can impact drug design.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Anderson AC (2003) The process of structure-based drug design. Chem Biol 10:787–797
Singh J, Petter RC, Baillie TA et al (2011) The resurgence of covalent drugs. Nat Rev Drug Discov 10:307–317
Bissantz C, Kuhn B, Stahl M (2010) A medicinal Chemist’s guide to molecular interactions. J Med Chem 53:5061–5084
Ferreira de Freitas R, Schapira M (2017) A systematic analysis of atomic protein–ligand interactions in the PDB. Med Chem Commun 8:1970–1981
Raha K, Peters MB, Wang B et al (2007) The role of quantum mechanics in structure-based drug design. Drug Discov Today 12:725–731
Kitaura K, Ikeo E, Asada T et al (1999) Fragment molecular orbital method: an approximate computational method for large molecules. Chem Phys Lett 313:701–706
Fox JM, Zhao M, Fink MJ et al (2018) The molecular origin of enthalpy/entropy compensation in biomolecular recognition. Annu Rev Biophys 47:223–250
Groom CR, Bruno IJ, Lightfoot MP et al (2016) The Cambridge structural database. Acta Crystallogr B 72:171–179
Berman HM, Westbrook J, Feng Z et al (2000) The Protein Data Bank. Nucleic Acids Res 28:235–242
Glasstone S (1937) The structure of some molecular complexes in the liquid phase. Trans Faraday Soc 33:200–206
IUPAC—hydrogen bond (HT07050). https://goldbook.iupac.org/terms/view/HT07050
Linus P (1931) The nature of the chemical bond. Application of results obtained from the quantum mechanics and from a theory of paramagnetic susceptibility to the structure of molecules. J Am Chem Soc 53:1367–1400
Lippincott ER, Schroeder R (1955) One-dimensional model of the hydrogen bond. J Chem Phys 23:1099–1106
Desiraju GR, Steiner T (1999) The weak hydrogen bond in structural chemistry and biology. Oxford University Press/International Union of Crystallography, Oxford
Espinosa E, Molins E, Lecomte C (1998) Hydrogen bond strengths revealed by topological analyses of experimentally observed electron densities. Chem Phys Lett 285:170–173
Sutor DJ (1962) The C–H⋯O hydrogen bond in crystals. Nature 195:68–69
Sutor DJ (1963) 204. Evidence for the existence of C–H⋯O hydrogen bonds in crystals. J Chem Soc:1105–1110
Donohue J (1968) Selected topics in hydrogen bonding. In: Rich A, Davidson NR, Pauling L (eds) Structural chemistry and molecular biology. W. H. Freeman, San Francisco
Taylor R, Kennard O (1982) Crystallographic evidence for the existence of CH⋯O, CH⋯N and CH⋯Cl hydrogen bonds. J Am Chem Soc 104:5063–5070
Desiraju GR (1991) The C-H⋯O hydrogen bond in crystals: what is it? Acc Chem Res 24:290–296
Steiner T (1997) Unrolling the hydrogen bond properties of C–H···O interactions. Chem Commun 8:727–734
Pierce AC, Sandretto KL, Bemis GW (2002) Kinase inhibitors and the case for CH⋯O hydrogen bonds in protein–ligand binding. Proteins 49:567–576
Pierce AC, ter Haar E, Binch HM et al (2005) CH···O and CH···N hydrogen bonds in ligand design: a novel Quinazolin-4-ylthiazol-2-ylamine protein kinase inhibitor. J Med Chem 48:1278–1281
Hunter CA, Sanders JKM (1990) The nature of π–π Interactions. J Am Chem Soc 112:5525–5534
Sinnokrot MO, Valeev EF, Sherrill CD (2002) Estimates of the ab initio limit for π–π interactions: the benzene dimer. J Am Chem Soc 124:10887–10893
Taylor RD, MacCoss M, Lawson ADG (2014) Rings in Drugs. J Med Chem 57:5845–5859
Huber RG, Margreiter MA, Fuchs JE et al (2014) Heteroaromatic π-stacking energy landscapes. J Chem Inf Model 54:1371–1379
Sinnokrot MO, Sherrill CD (2004) Substituent effects in π−π interactions: Sandwich and T-shaped configurations. J Am Chem Soc 126:7690–7697
Liao S-M, Du Q-S, Meng J-Z et al (2013) The multiple roles of histidine in protein interactions. Chem Cent J 7:44
Harder M, Kuhn B, Diederich F (2013) Efficient stacking on protein amide fragments. ChemMedChem 8:397–404
Vernon RM, Chong PA, Tsang B et al (2018) Pi-pi contacts are an overlooked protein feature relevant to phase separation. elife 7:e31486
Kumar K, Woo SM, Siu T et al (2018) Cation–π interactions in protein–ligand binding: theory and data-mining reveal different roles for lysine and arginine. Chem Sci 9:2655–2665
Singh NJ, Min SK, Kim DY et al (2009) Comprehensive energy analysis for various types of π-interaction. J Chem Theory Comput 5:515–529
Imai YN, Inoue Y, Nakanishi I et al (2008) Cl–π interactions in protein–ligand complexes. Protein Sci 17:1129–1137
Li P, Maier JM, Vik EC et al (2017) Stabilizing fluorine–π interactions. Angew Chem Int Ed Engl 56:7209–7212
Dougherty DA (2013) The Cation−π interaction. Acc Chem Res 46:885–893
Gallivan JP, Dougherty DA (1999) Cation-π interactions in structural biology. Proc Natl Acad Sci U S A 96:9459–9464
Dougherty DA (2007) Cation-π interactions involving aromatic amino acids. J Nutr 137:1504S–1508S
Olsen JA, Balle T, Gajhede M et al (2014) Molecular recognition of the neurotransmitter acetylcholine by an acetylcholine binding protein reveals determinants of binding to nicotinic acetylcholine receptors. PLoS One 9:e91232
Wilcken R, Zimmermann MO, Lange A et al (2013) Principles and applications of halogen bonding in medicinal chemistry and chemical biology. J Med Chem 56:1363–1388
Shinada NK, de Brevern AG, Schmidtke P (2019) Halogens in protein–ligand binding mechanism: a structural perspective. J Med Chem. In Press
Coates M, Ho PS (2016) Computational tools to model halogen bonds in medicinal chemistry. J Med Chem 59:1655–1670
Kurczab R, Canale V, Satała G et al (2018) Amino acid hot spots of halogen bonding: a combined theoretical and experimental case study of the 5-HT7 receptor. J Med Chem 61:8717–8733
Paulini R, Müller K, Diederich F (2005) Orthogonal multipolar interactions in structural chemistry and biology. Angew Chem Int Ed Engl 44:1788–1805
Olsen JA, Banner DW, Seiler P et al (2003) A fluorine scan of thrombin inhibitors to map the fluorophilicity/fluorophobicity of an enzyme active site: evidence for C-F⋯C=O interactions. Angew Chem Int Ed Engl 42:2507–2511
Pollock J, Borkin D, Lund G et al (2015) Rational design of orthogonal multipolar interactions with fluorine in protein–ligand complexes. J Med Chem 58:7465–7474
Heifetz A, James T, Southey M et al (2019) Characterising GPCR–ligand interactions using a fragment molecular orbital-based approach. Curr Opin Struct Biol 55:85–92
Heifetz A, Aldeghi M, Chudyk EI et al (2016) Using the fragment molecular orbital method to investigate agonist–orexin-2 receptor interactions. Biochem Soc Trans 44:574–581
Zhang J-X, Sheong FK, Lin Z (2018) Unravelling chemical interactions with principal interacting orbital analysis. Chemistry 24:9639–9650
Xu Z, Zhang Q, Shi J et al (2019) Underestimated noncovalent interactions in protein data Bank. J Chem Inf Model. In Press
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Anighoro, A. (2020). Underappreciated Chemical Interactions in Protein–Ligand Complexes. In: Heifetz, A. (eds) Quantum Mechanics in Drug Discovery. Methods in Molecular Biology, vol 2114. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0282-9_5
Download citation
DOI: https://doi.org/10.1007/978-1-0716-0282-9_5
Published:
Publisher Name: Humana, New York, NY
Print ISBN: 978-1-0716-0281-2
Online ISBN: 978-1-0716-0282-9
eBook Packages: Springer Protocols