7ZLC

Crystal Structure of Unlinked NS2B_NS3 Protease from Zika Virus in Complex with Inhibitor MI-2224

Summary for 7ZLC

• Entry DOI: 10.2210/pdb7zlc/pdb
• Descriptor: Serine protease subunit NS2B, Serine protease NS3, (2~{S})-6-azanyl-~{N}-[(2~{S})-6-azanyl-1-(5-carbamimidamidopentylamino)-1-oxidanylidene-hexan-2-yl]-2-(propanoylamino)hexanamide, ... (4 entities in total)
• Functional Keywords: flavivirin, serine protease, viral protein, ns2b-ns3, zika virus
• Biological source: Zika virus; More
• Total number of polymer chains: 2
• Total formula weight: 25359.60

Authors

Huber, S.,Steinmetzer, T. (deposition date: 2022-04-14, release date: 2022-12-28, Last modification date: 2024-02-07)

Primary citation

Hammerschmidt, S.J.,Huber, S.,Braun, N.J.,Lander, M.,Steinmetzer, T.,Kersten, C.
Thermodynamic characterization of a macrocyclic Zika virus NS2B/NS3 protease inhibitor and its acyclic analogs.
Arch Pharm, 356:e2200518-e2200518, 2023

PubMed Abstract: 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.

PubMed: 36480352
DOI: 10.1002/ardp.202200518

Experimental method

X-RAY DIFFRACTION (1.75 Å)