Research output: Contribution to journal › Article › peer-review
Lucky Switcheroo : Dramatic Potency and Selectivity Improvement of Imidazoline Inhibitors of Human Carbonic Anhydrase VII. / Kalinin, Stanislav; Kopylov, Stanislav; Tuccinardi, Tiziano; Sapegin, Alexander; Dar'In, Dmitry; Angeli, Andrea; Supuran, Claudiu T.; Krasavin, Mikhail.
In: ACS Medicinal Chemistry Letters, Vol. 8, No. 10, 12.10.2017, p. 1105-1109.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Lucky Switcheroo
T2 - Dramatic Potency and Selectivity Improvement of Imidazoline Inhibitors of Human Carbonic Anhydrase VII
AU - Kalinin, Stanislav
AU - Kopylov, Stanislav
AU - Tuccinardi, Tiziano
AU - Sapegin, Alexander
AU - Dar'In, Dmitry
AU - Angeli, Andrea
AU - Supuran, Claudiu T.
AU - Krasavin, Mikhail
N1 - Funding Information: *Tel: +7 9313617872. Fax: +7 812 4286939. E-mail: m. krasavin@spbu.ru *Tel: +39 0554573729. Fax +39 0554573385. E-mail: claudiu. supuran@unifi.it. ORCID Tiziano Tuccinardi: 0000-0002-6205-4069 Claudiu T. Supuran: 0000-0003-4262-0323 Mikhail Krasavin: 0000-0002-0200-4772 Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding This research was supported by the Russian Science Foundation (project grant 14-50-00069). Notes The authors declare no competing financial interest. Publisher Copyright: © 2017 American Chemical Society. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2017/10/12
Y1 - 2017/10/12
N2 - A substantial improvement of potency and selectivity of imidazoline-based inhibitors of hCA VII (a promising target for the treatment of seizures and neuropathic pain) was achieved by simply switching the position of the benzenesulfonamide moiety from N1 (as in the earlier reported series) to C2. Selectivity indices vs the off-target isoforms (hCA I, I, I and IV) greater than 100 were reached, which is exceedingly rare for hCA VII inhibitors. The drastic profile improvement of the new series has been rationalized by an additional hydrogen bonding with the nonconserved Q69 residue in the active site of hCA VII (absent in the other three isoforms studied), which also results in a favorable accommodation of the inhibitor's lipophilic periphery in the nearby hydrophobic pocket. The robustness of the docking simulations was tested and confirmed by molecular dynamics simulations.
AB - A substantial improvement of potency and selectivity of imidazoline-based inhibitors of hCA VII (a promising target for the treatment of seizures and neuropathic pain) was achieved by simply switching the position of the benzenesulfonamide moiety from N1 (as in the earlier reported series) to C2. Selectivity indices vs the off-target isoforms (hCA I, I, I and IV) greater than 100 were reached, which is exceedingly rare for hCA VII inhibitors. The drastic profile improvement of the new series has been rationalized by an additional hydrogen bonding with the nonconserved Q69 residue in the active site of hCA VII (absent in the other three isoforms studied), which also results in a favorable accommodation of the inhibitor's lipophilic periphery in the nearby hydrophobic pocket. The robustness of the docking simulations was tested and confirmed by molecular dynamics simulations.
KW - 2-imidazolines
KW - carbonic anhydrase inhibitors
KW - docking simulation
KW - hydrogen bonding
KW - isoform selectivity
KW - molecular dynamics
KW - N-arylimidazolines
KW - nonconserved residue
KW - primary sulfonamide
KW - Privileged scaffold
KW - zinc binding group
UR - http://www.scopus.com/inward/record.url?scp=85031306336&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.7b00300
DO - 10.1021/acsmedchemlett.7b00300
M3 - Article
AN - SCOPUS:85031306336
VL - 8
SP - 1105
EP - 1109
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 10
ER -
ID: 9300607