High Throughput Methods to Measure the Propensity of Compounds to Form Intramolecular Hydrogen Bonding

Overview

Journal Medchemcomm

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2018 Aug 16

PMID 30108824

Citations 7

Authors

Giulia Caron

Maura Vallaro

Giuseppe Ermondi

Affiliations

Soon will be listed here.

Abstract

Implementation of IMHB considerations in drug discovery needs robust and validated descriptors to experimentally verify the propensity of compounds to exhibit IMHBs. The first part of the paper presents an overview of the most common techniques to measure the propensity of compounds to form IMHBs. Then we review and discuss recently proposed high throughput (HT) physicochemical descriptors ( Δlog , EPSA and log '80 PLRP-S) which provide the same information. Analysis of the available data enabled us to extract guidelines for the application of these descriptors in drug discovery programs.

Citing Articles

Membrane Permeability in a Large Macrocyclic Peptide Driven by a Saddle-Shaped Conformation.

Faris J, Adaligil E, Popovych N, Ono S, Takahashi M, Nguyen H J Am Chem Soc. 2024; 146(7):4582-4591.

PMID: 38330910 PMC: 10885153. DOI: 10.1021/jacs.3c10949.

Oral Absorption of Middle-to-Large Molecules and Its Improvement, with a Focus on New Modality Drugs.

Asano D, Takakusa H, Nakai D Pharmaceutics. 2024; 16(1).

PMID: 38258058 PMC: 10820198. DOI: 10.3390/pharmaceutics16010047.

Molecular chameleons in drug discovery.

Poongavanam V, Wieske L, Peintner S, Erdelyi M, Kihlberg J Nat Rev Chem. 2023; 8(1):45-60.

PMID: 38123688 DOI: 10.1038/s41570-023-00563-1.

Steering New Drug Discovery Campaigns: Permeability, Solubility, and Physicochemical Properties in the bRo5 Chemical Space.

Caron G, Kihlberg J, Goetz G, Ratkova E, Poongavanam V, Ermondi G ACS Med Chem Lett. 2021; 12(1):13-23.

PMID: 33488959 PMC: 7812602. DOI: 10.1021/acsmedchemlett.0c00581.

Machine learning models for hydrogen bond donor and acceptor strengths using large and diverse training data generated by first-principles interaction free energies.

Bauer C, Schneider G, Goller A J Cheminform. 2021; 11(1):59.

PMID: 33430967 PMC: 6737620. DOI: 10.1186/s13321-019-0381-4.

References

Shalaeva M, Caron G, Abramov Y, OConnell T, Plummer M, Yalamanchi G . Integrating intramolecular hydrogen bonding (IMHB) considerations in drug discovery using ΔlogP as a tool. J Med Chem. 2013; 56(12):4870-9. DOI: 10.1021/jm301850m. View

Lessene G, Smith B, Gable R, Baell J . Characterization of the two fundamental conformations of benzoylureas and elucidation of the factors that facilitate their conformational interchange. J Org Chem. 2009; 74(17):6511-25. DOI: 10.1021/jo900871a. View

Manallack D, Prankerd R, Nassta G, Ursu O, Oprea T, Chalmers D . A chemogenomic analysis of ionization constants--implications for drug discovery. ChemMedChem. 2013; 8(2):242-55. PMC: 3777741. DOI: 10.1002/cmdc.201200507. View

Rafi S, Hearn B, Vedantham P, Jacobson M, Renslo A . Predicting and improving the membrane permeability of peptidic small molecules. J Med Chem. 2012; 55(7):3163-9. PMC: 3325374. DOI: 10.1021/jm201634q. View

Carrupt P, Testa B, Bechalany A, El Tayar N, Descas P, Perrissoud D . Morphine 6-glucuronide and morphine 3-glucuronide as molecular chameleons with unexpected lipophilicity. J Med Chem. 1991; 34(4):1272-5. DOI: 10.1021/jm00108a005. View

Lipinski C, Lombardo F, Dominy B, Feeney P . Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001; 46(1-3):3-26. DOI: 10.1016/s0169-409x(00)00129-0. View

Bockus A, Lexa K, Pye C, Kalgutkar A, Gardner J, Hund K . Probing the Physicochemical Boundaries of Cell Permeability and Oral Bioavailability in Lipophilic Macrocycles Inspired by Natural Products. J Med Chem. 2015; 58(11):4581-9. DOI: 10.1021/acs.jmedchem.5b00128. View

Gramse G, Dols-Perez A, Edwards M, Fumagalli L, Gomila G . Nanoscale measurement of the dielectric constant of supported lipid bilayers in aqueous solutions with electrostatic force microscopy. Biophys J. 2013; 104(6):1257-62. PMC: 3602784. DOI: 10.1016/j.bpj.2013.02.011. View

Over B, McCarren P, Artursson P, Foley M, Giordanetto F, Gronberg G . Impact of stereospecific intramolecular hydrogen bonding on cell permeability and physicochemical properties. J Med Chem. 2014; 57(6):2746-54. PMC: 3968888. DOI: 10.1021/jm500059t. View

10.

Kuhn B, Mohr P, Stahl M . Intramolecular hydrogen bonding in medicinal chemistry. J Med Chem. 2010; 53(6):2601-11. DOI: 10.1021/jm100087s. View

11.

Haynes C, Busschaert N, Kirby I, Herniman J, Light M, Wells N . Acylthioureas as anion transporters: the effect of intramolecular hydrogen bonding. Org Biomol Chem. 2013; 12(1):62-72. DOI: 10.1039/c3ob41522h. View

12.

Goetz G, Farrell W, Shalaeva M, Sciabola S, Anderson D, Yan J . High throughput method for the indirect detection of intramolecular hydrogen bonding. J Med Chem. 2014; 57(7):2920-9. DOI: 10.1021/jm401859b. View

13.

Rezai T, Bock J, Zhou M, Kalyanaraman C, Lokey R, Jacobson M . Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: successful in silico prediction of the relative permeabilities of cyclic peptides. J Am Chem Soc. 2006; 128(43):14073-80. DOI: 10.1021/ja063076p. View

14.

Hyung S, Feng X, Che Y, Stroh J, Shapiro M . Detection of conformation types of cyclosporin retaining intramolecular hydrogen bonds by mass spectrometry. Anal Bioanal Chem. 2014; 406(24):5785-94. DOI: 10.1007/s00216-014-8023-1. View

15.

Sciabola S, Goetz G, Bai G, Rogers B, Gray D, Duplantier A . Systematic N-methylation of oxytocin: Impact on pharmacology and intramolecular hydrogen bonding network. Bioorg Med Chem. 2016; 24(16):3513-20. DOI: 10.1016/j.bmc.2016.05.062. View

16.

Caron G, Vallaro M, Ermondi G, Goetz G, Abramov Y, Philippe L . A Fast Chromatographic Method for Estimating Lipophilicity and Ionization in Nonpolar Membrane-Like Environment. Mol Pharm. 2016; 13(3):1100-10. DOI: 10.1021/acs.molpharmaceut.5b00910. View

17.

Desai P, Raub T, Blanco M . How hydrogen bonds impact P-glycoprotein transport and permeability. Bioorg Med Chem Lett. 2012; 22(21):6540-8. DOI: 10.1016/j.bmcl.2012.08.059. View

18.

Whitty A, Zhong M, Viarengo L, Beglov D, Hall D, Vajda S . Quantifying the chameleonic properties of macrocycles and other high-molecular-weight drugs. Drug Discov Today. 2016; 21(5):712-7. PMC: 5821503. DOI: 10.1016/j.drudis.2016.02.005. View

19.

Goetz G, Shalaeva M, Caron G, Ermondi G, Philippe L . Relationship between Passive Permeability and Molecular Polarity Using Block Relevance Analysis. Mol Pharm. 2016; 14(2):386-393. DOI: 10.1021/acs.molpharmaceut.6b00724. View

20.

Baxter N, Williamson M . Temperature dependence of 1H chemical shifts in proteins. J Biomol NMR. 1997; 9(4):359-69. DOI: 10.1023/a:1018334207887. View