Ionization Constants and Ionization Profiles☆

Comer, John; Manallack, David T.

doi:10.1016/b978-0-12-409547-2.11233-8

Cited by 3 publications

(2 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2c) revealed that 13 is encapsulated in the host pocket with its alkyl chain in the hydrophobic tubular region of the host cavity, and, unmistakably, with its carbonyl oxygen H-bonded to the inwardly pointing OH group in the deep cavity of the host, with the CO•••HO distance of 1.941 Å, perfectly in the range of a typical H-bond length 35 . Thus, the complex 13⊂endo- Amides are commonly seen in drug molecules 36 . Amide functional groups have weak basic and acidic possibilities 37 .…”

Section: Resultsmentioning

confidence: 99%

Pillar[5]arene-Derived endo-Functionalized Molecular Tube for Mimicking Protein–Ligand Interactions

et al. 2021

View full text Add to dashboard Cite

Arti cial tubular molecular pockets bearing polar functionalities on their inner surface are useful model systems for understanding the mechanisms of protein-ligand interactions in living systems. We herein report a pillar [5]arene-derived molecular tube, [P4-(OH)BPO], whose endo conformational isomer endo-[P4-(OH)BPO] possesses an inwardly pointing hydrogen-bond (H-bond) donor (OH) in its deep cavity, a strong H-bond acceptor (C=O) on the predominantly hydrophobic inner surface, rendering it a perfect protein binding pocket mimetic. By measuring the binding a nity of this pocket-mimetic tube, we screened a library of various shape-complementary organic guests (1-38) resembling the fragment ligands in fragment-based drug design (FBDD). On the basis of the data for "fragment-pocket" complexes (1-38)⊂endo-[P4-(OH)BPO], two rationally designed "lead molecules" (39 and 40) were identi ed to be able to enhance binding a nity signi cantly by forming H-bonds with both the donor and acceptor of endo-[P4-(OH)BPO]. The described work opens new avenues for developing pillar[n]arene-derived protein binding pocket-mimetic systems for studies on protein-ligand interactions and mechanisms of enzymatic reactions.

show abstract

Section: Resultsmentioning

confidence: 99%

Pillar[5]arene-Derived endo-Functionalized Molecular Tube for Mimicking Protein–Ligand Interactions

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The most common methods for measuring small molecule p K a s are UV-absorbance spectroscopy (UV-metric titration) [28–30], potentiometry (pH-metric titration) [30, 31], capillary electrophoresis [32, 33], and NMR spectroscopy [21], with NMR being the most time-consuming approach. Other, less popular p K a measurement techniques include conductometry, HPLC, solubility or partition based estimations, calorimetry, fluorometry, and polarimetry [34].…”

Section: Introductionmentioning

confidence: 99%

pKa measurements for the SAMPL6 prediction challenge for a set of kinase inhibitor-like fragments

Işık

Levorse

Rustenburg

et al. 2018

J Comput Aided Mol Des

View full text Add to dashboard Cite

Determining the net charge and protonation states populated by a small molecule in an environment of interest or the cost of altering those protonation states upon transferto another environment is a prerequisite for predicting its physicochemical and pharmaceutical properties. The environment of interest can be aqueous, an organic solvent, a protein binding site, or a lipid bilayer. Predicting the protonation state of a small molecule is essential to predicting its interactions with biological macromolecules using computational models. Incorrectly modeling the dominant protonation state, shifts in dominant protonation state, or the population of significant mixtures of protonation states can lead to large modeling errors that degrade the accuracy of physical modeling. Low accuracy hinders the use of physical modeling approaches for molecular design. For small molecules, the acid dissociation constant (pKa) is the primary quantity needed to determine the ionic states populated by a molecule in an aqueous solution at a given pH. As a part of SAMPL6 community challenge, we organized a blind pKa prediction component to assess the accuracy with which contemporary pKa prediction methods can predict this quantity, with the ultimate aim of assessing the expected impact on modeling errors this would induce. While a multitude of approaches for predicting pKa values currently exist, predicting the pKas of drug-like molecules can be difficult due to challenging properties such as multiple titratable sites, heterocycles, and tautomerization. For this challenge, we focused on set of 24 small molecules selected to resemble selective kinase inhibitors—an important class of therapeutics replete with titratable moieties. Using a Sirius T3 instrument that performs automated acid- base titrations, we used UV absorbance-based pKa measurements to construct a high-quality experimental reference dataset of macroscopic pKas for the evaluation of computational pKa prediction methodologies that was utilized in the SAMPL6 pKa challenge. For several compounds in which the microscopic protonation states associated with macroscopic pKas were ambiguous, we performed follow-up NMR experiments to disambiguate the microstates involved in the transition. This dataset provides a useful standard benchmark dataset for the evaluation of pKa prediction methodologies on kinase inhibitor-like compounds.

show abstract

pK_a measurements for the SAMPL6 prediction challenge for a set of kinase inhibitor-like fragments

Işık

Levorse

Rustenburg

et al. 2018

Preprint

View full text Add to dashboard Cite

we used UV absorbance-based pK a measurements to construct a high-quality experimental reference dataset 36 of macroscopic pK a s for the evaluation of computational pK a prediction methodologies that was utilized in CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which . http://dx.doi.org/10.1101/368787 doi: bioRxiv preprint first posted online Jul. 13, 2018;

show abstract

Ionization Constants and Ionization Profiles☆

Cited by 3 publications

References 81 publications

Pillar[5]arene-Derived endo-Functionalized Molecular Tube for Mimicking Protein–Ligand Interactions

Pillar[5]arene-Derived endo-Functionalized Molecular Tube for Mimicking Protein–Ligand Interactions

pKa measurements for the SAMPL6 prediction challenge for a set of kinase inhibitor-like fragments

pK_a measurements for the SAMPL6 prediction challenge for a set of kinase inhibitor-like fragments

Contact Info

Product

Resources

About