Thermodynamic characterization of a macrocyclic Zika virus NS2B/NS3 protease inhibitor and its acyclic analogs

被引:5
作者
Hammerschmidt, Stefan J. J. [1 ]
Huber, Simon [2 ]
Braun, Niklas J. J. [2 ]
Lander, Marc [1 ]
Steinmetzer, Torsten [2 ]
Kersten, Christian [1 ]
机构
[1] Johannes Gutenberg Univ Mainz, Inst Pharmaceut & Biomed Sci, Staudingerweg 5, D-55128 Mainz, Germany
[2] Philipps Univ, Inst Pharmaceut Chem, Marburg, Germany
关键词
crystallization; macrocycles; molecular dynamics; thermodynamics; Zika NS2B; NS3; protease; PRESSURE PERTURBATION CALORIMETRY; MOLECULAR-DYNAMICS; NS2B-NS3; PROTEASE; PEPTIDOMIMETIC INHIBITORS; LIGAND PREORGANIZATION; TITRATION CALORIMETRY; SIDE-CHAIN; BINDING; WATER; AFFINITY;
D O I
10.1002/ardp.202200518
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Cyclization of small molecules is a widely applied strategy in drug design for ligand optimization to improve affinity, as it eliminates the putative need for structural preorganization of the ligand before binding, or to improve pharmacokinetic properties. In this work, we provide a deeper insight into the binding thermodynamics of a macrocyclic Zika virus NS2B/NS3 protease inhibitor and its linear analogs. Characterization of the thermodynamic binding profiles by isothermal titration calorimetry experiments revealed an unfavorable entropy of the macrocycle compared to the open linear reference ligands. Molecular dynamic simulations and X-ray crystal structure analysis indicated only minor benefits from macrocyclization to fixate a favorable conformation, while linear ligands retained some flexibility even in the protein-bound complex structure, possibly explaining the initially surprising effect of a higher entropic penalty for the macrocyclic ligand.
引用
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页数:10
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