Handling drug-target selectivity: A study on ureido containing Carbonic Anhydrase inhibitors

Akgül, Özlem; Singh, Srishti; Andring, Jacob T.; McKenna, Robert; Selleri, Silvia; Carta, Fabrizio; Angeli, Andrea; Supuran, Claudiu T.

doi:10.1016/j.ejmech.2020.113035

Cited by 12 publications

(9 citation statements)

References 21 publications

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“…The inhibition constants were obtained by non‐linear least‐squares methods using PRISM 3 and the Cheng‐Prusoff equation as reported earlier and represent the mean from at least three different determinations. All CA isoforms were recombinant proteins obtained inhouse, as reported earlier [5,8,10–12] …”

Section: Methodsmentioning

confidence: 99%

“…Whereas, small molecules can readily be use as valid alternatives, although they maintain to some extent a certain degree of un‐selectivity which may be useful and properly enhanced/directed when multiple and/or functional cooperative biological targets for a disease are addressed (i. e. polypharmacology). In this context our groups largely contributed to decipher at the atomic level the principles governing the binding modes of variegate molecular scaffolds onto the human Carbonic Anhydrases (hCAs, EC 4.2.1.1) which are linked to many diseases, such as cancers [8–13] . This study reports for the first‐time deep structure‐activity relationships (SARs) referred to classical hCA inhibitors (CAIs) of the primary sulfonamide type bearing ureido alkoxy tails.…”

Section: Introductionmentioning

confidence: 99%

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Small Molecule Alkoxy Oriented Selectiveness on Human Carbonic Anhydrase II and IX Inhibition

et al. 2022

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We report aryl sulfonamide inhibitors of human carbonic anhydrase (hCA; EC 4.2.1.1) enzymes containing short ureido alkoxy tails. The inhibition potency of such compounds was investigated in vitro on the major hCA isoforms (i.e. I, II, IX, and XII). A selection of the most potent inhibitory derivatives against the hCA IX isoform (i.e. 5a, 5c, and 6c) was studied, and their binding modes on either hCA II and IX-mimic isoform were assessed by X-ray crystallography on the corresponding ligand/ protein adducts. This study adds to the field of developing hCA inhibitors at molecular level the critical interactions governing ligand selectivity.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Small Molecule Alkoxy Oriented Selectiveness on Human Carbonic Anhydrase II and IX Inhibition

et al. 2022

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“…The tail approach was virtually the only strategy used to obtain CAIs from the moment it was disclosed, and it has been adopted by research groups all over the world 71,[75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91] . For space reasons only a limited number of such research was cited here, as the field was recently reviewed 14,48 .…”

Section: Sulphonamides and Other Zinc Binders The Tail Approachmentioning

confidence: 99%

Reconsidering anion inhibitors in the general context of drug design studies of modulators of activity of the classical enzyme carbonic anhydrase

Nocentini

Carta

Winum

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Inorganic anions inhibit the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) generally by coordinating to the active site metal ion. Cyanate was reported as a non-coordinating CA inhibitor but those erroneous results were subsequently corrected by another group. We review the anion CA inhibitors (CAIs) in the more general context of drug design studies and the discovery of a large number of inhibitor classes and inhibition mechanisms, including zinc binders (sulphonamides and isosteres, dithiocabamates and isosteres, thiols, selenols, benzoxaboroles, ninhydrins, etc.); inhibitors anchoring to the zinc-coordinated water molecule (phenols, polyamines, sulfocoumarins, thioxocoumarins, catechols); CAIs occluding the entrance to the active site (coumarins and derivatives, lacosamide), as well as compounds that bind outside the active site. All these new chemotypes integrated with a general procedure for obtaining isoform-selective compounds (the tail approach) has resulted, through the guidance of rigorous X-ray crystallography experiments, in the development of highly selective CAIs for all human CA isoforms with many pharmacological applications.

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“…Like human -CAs, SmCA can be efficiently targeted by (hetero)arylsulfonamide-type chemical scaffolds belonging to newly synthesized compounds or to repurposed drugs (Angeli et al, 2020(Angeli et al, , 2021. Sulfonamides and their bioisosteres are the main inhibitors of CA, with inhibition constants in the nanomolar range, because of the presence of an undoubtedly efficacious zinc-binding group (ZBG; Biswas et al, 2011;Mishra et al, 2020;Akgul et al, 2021), although an increased isoform selectivity must be achieved by the introduction of additional moieties on the aryl ring, as in the tail approach.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Schistosoma mansoni carbonic anhydrase by the antiparasitic drug clorsulon: X-ray crystallographic and in vitro studies

Ferraroni

Angeli

Carradori

2022

Acta Cryst Sect D Struct Biol

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Clorsulon is an anthelmintic drug that is clinically used against Fasciola hepatica. Due to the presence of two sulfonamide moieties in its core nucleus, which are well recognized as zinc-binding groups, it was proposed that it may be efficacious in the inhibition of parasite carbonic anhydrases (CAs). Proteomic analyses revealed the presence of CA in the tegument of Schistosoma mansoni, and recently the druggability of this target was explored by testing the inhibitory activities of several sulfonamide-based derivatives. According to the principles of drug repurposing, the aim was to demonstrate a putative new mechanism of action of clorsulon and thus widen its antiparasitic spectrum. For this purpose, the inhibitory activity and isoform selectivity of clorsulon was studied using human CA I and S. mansoni CA, revealing different modes of binding of clorsulon that explain its inhibitory potency against the two enzymes. The information obtained in this study could be crucial in the design of more active and selective derivatives.

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Handling drug-target selectivity: A study on ureido containing Carbonic Anhydrase inhibitors

Cited by 12 publications

References 21 publications

Small Molecule Alkoxy Oriented Selectiveness on Human Carbonic Anhydrase II and IX Inhibition

Small Molecule Alkoxy Oriented Selectiveness on Human Carbonic Anhydrase II and IX Inhibition

Reconsidering anion inhibitors in the general context of drug design studies of modulators of activity of the classical enzyme carbonic anhydrase

Inhibition of Schistosoma mansoni carbonic anhydrase by the antiparasitic drug clorsulon: X-ray crystallographic and in vitro studies

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