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@ARTICLE{Rasheed:617347,
author = {Rasheed, Saima and Huda, Noor ul and Fisher, S. Zoë and
Falke, Sven and Gul, Sadaf and Ahmad, Malik Shoaib and
Choudhary, M. Iqbal},
title = {{I}dentification, crystallization, and first {X}-ray
structure analyses of phenyl boronic acid-based inhibitors
of human carbonic anhydrase-{II}},
journal = {International journal of biological macromolecules},
volume = {267},
issn = {0141-8130},
address = {New York, NY [u.a.]},
publisher = {Elsevier},
reportid = {PUBDB-2024-06713},
pages = {131268},
year = {2024},
note = {Waiting for fulltext},
abstract = {Human carbonic anhydrases (hCAs) play a central role in
various physiological processes in the human body. HCAs
catalyze the reversible hydration of CO2 into HCO3−, and
hence maintains the fluid and pH balance. Overexpression of
CA II is associated with diseases, such as glaucoma, and
epilepsy. Therefore, CAs are important clinical targets and
inhibition of different isoforms, especially hCA II is used
in treatment of glaucoma, altitude sickness, and epilepsy.
Therapeutically used CA inhibitors (CAI) are
sulfonamide-based, such as acetazolamide, dichlorphenamide,
methazolamide, ethoxzolamide, etc. However, they exhibit
several undesirable effects such as numbness, tingling of
extremities, malaise, metallic taste, fatigue, renal
calculi, and metabolic acidosis. Therefore, there is an
urgent need to identify safe and effective inhibitors of the
hCAs. In this study, different phenyl boronic acids 1–5
were evaluated against bovine (bCA II) and hCA II. Among
all, compound 1 (4-acetylphenyl boronic acid) was found to
be active against bCAII and hCA II with IC50 values of 246
± 0.48 and 281.40 ± 2.8 μM, respectively, while the
remaining compounds were found in-active. Compound 1 was
identified as competitive inhibitor of hCA II enzyme (Ki =
283.7 ± 0.002 μM). Additionally, compound 1 was found to
be non-toxic against BJ Human fibroblast cell line. The
X-ray crystal structure for hCA II in-complex with compound
1 was evaluated to a resolution of 2.6 Å. In fact, this the
first structural analysis of a phenyl boron-based inhibitor
bound to hCA II, allowing an additional structure-activity
analysis of the compounds. Compound 1 was found to be
directly bound in the active site of hCA II by interacting
with His94, His119, and Thr199 residues. In addition, a bond
of 3.11 Å between the zinc ion and coordinated boron atom
of the boronic acid moiety of compound 1 was also observed,
contributing to binding affinity of compound 1 for hCA II.},
cin = {FS-CFEL-1-BMX},
ddc = {570},
cid = {I:(DE-H253)FS-CFEL-1-BMX-20210408},
pnm = {633 - Life Sciences – Building Blocks of Life: Structure
and Function (POF4-633)},
pid = {G:(DE-HGF)POF4-633},
experiment = {EXP:(DE-MLZ)External-20140101},
typ = {PUB:(DE-HGF)16},
pubmed = {38580011},
UT = {WOS:001285901200001},
doi = {10.1016/j.ijbiomac.2024.131268},
url = {https://bib-pubdb1.desy.de/record/617347},
}