Professor
Supervisor of Doctorate Candidates
Supervisor of Master's Candidates
Hits:
Impact Factor3.461
DOI number:10.1016/j.bmc.2022.116864
Journal:Bioorganic & Medicinal Chemistry
Abstract:Early potential evaluation of lead compounds is critical to decrease downstream lead-optimization cycle times and clinical attrition rates for drug development. This increasingly necessitates the methodologies for accurately evaluating the potential compounds. This work immobilized β2-adrenoceptor (β2-AR) onto microspheres through Halo-tag mediated reaction. Characterizing the resulting microspheres by elemental and functional analysis, we utilized the immobilized receptor to determine the thermodynamics of terbutaline, tulobuterol, clorprenaline, salbutamol, and methoxyphenamine. The association constants correlated to their capacity factors on the column containing the immobilized β2-AR, thus providing a possibility for early potential evaluation of lead compounds from complex matrices like a DNA-encoded library. By this model, the lead compound (XC267) was predicted to have an association constant higher than terbutaline, salbutamol, and methoxyphenamine, but lower than tulobuterol and clorprenaline. The binding interaction between XC267 and β2-AR is a spontaneous endothermic process with an association constant of (6.62 ± 0.13) × 104 Mℑ 1 at 37 ◦C. The change of Gibbs free energy(ΔGθ), enthalpy change (ΔHθ), and entropy change (ΔSθ) was ± 28.49 kJ/mol, ± 10.58 kJ/mol, and 57.79 J/moL⋅K at 37 ◦C. By the semi-empirical rule of Ross, the driving force of the interaction between XC267 and β2-AR was electrostatic interaction. Such binding force was also achieved by molecular docking. These results suggested that XC267 is a candidate to treat asthma by specific binding to β2-AR. We reasoned that receptor chromatography is able to the early potential evaluation of lead compounds from complex matrices.
Indexed by:Journal paper
Discipline:Medicine
First-Level Discipline:Chinese Herbology
Document Type:J
Volume:68
Issue:116864
Translation or Not:no
Date of Publication:2022-05-31
Included Journals:SCI
Pre One:Discovery of dual-target ligands binding to beta2-adrenoceptor and cysteinyl-leukotriene receptor for the potential treatment of asthma from natural products derived DNA-encoded library
Next One:Development of an Allostery Responsive Chromatographic Method for Screening Potential Allosteric Modulator of Beta2-adrenoceptor from a Natural Product-Derived DNA-Encoded Chemical Library