Steroids interfere with human carbonic anhydrase activity by using alternative binding mechanisms

Nocentini, Alessio; Bonardi, Alessandro; Gratteri, Paola; Cerra, Bruno; Gioiello, Antimo

doi:10.1080/14756366.2018.1512597

Cited by 71 publications

(35 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ligands were docked with the standard precision mode (SP) of Glide [43c] and the best 5 poses of each molecule retained as output. The best pose for each compound, evaluated in terms of coordination, hydrogen bond interactions and hydrophobic contacts, was refined with Prime [43d] with a VSGB solvation model considering the target flexible within 3 Å around the ligand [44–46] …”

Section: Methodsmentioning

confidence: 99%

Synthesis, Computational Studies and Assessment of in Vitro Activity of Squalene Derivatives as Carbonic Anhydrase Inhibitors

Clima¹,

Craciun²,

Angeli

et al. 2020

ChemMedChem

Self Cite

View full text Add to dashboard Cite

We report novel molecules incorporating the nontoxic squalene scaffold and different carbonic anhydrase inhibitors (CAIs). Potent inhibitory action, in the low‐nanomolar range, was detected against isoforms hCA II for sulfonamide derivatives, which proved to be selective against this isoform over the tumor‐associate hCA IX and XII isoforms. On the other hand, coumarin derivatives showed weak potency but high selectivity against the tumor‐associated isoform CA IX. These compounds are interesting candidates for preclinical evaluation in glaucoma or various tumors in which the two enzymes are involved. In addition, an in silico study of inhibitor‐bound hCA II revealed extensive interactions with the hydrophobic pocket of the active site and provided molecular insights into the binding properties of these new inhibitors.

show abstract

Section: Methodsmentioning

confidence: 99%

Synthesis, Computational Studies and Assessment of in Vitro Activity of Squalene Derivatives as Carbonic Anhydrase Inhibitors

Clima¹,

Craciun²,

Angeli

et al. 2020

ChemMedChem

Self Cite

View full text Add to dashboard Cite

show abstract

“…Additional inhibitors that have been developed exhibit a different inhibition mechanism: they anchor to the zinc-coordinated water molecule [ 104 , 105 ]. Polyamines, such as spermine and its derivatives [ 104 ], and the simple phenol [ 105 ] and many of its derivatives [ 106 , 107 , 108 , 109 ] together with polyphenols [ 110 ] inhibit CAs in this way. This inhibition mechanism is also shared by the sulfocoumarins, as demonstrated by Zalubovskis group [ 86 ] by using kinetic and crystallographic studies.…”

Section: Validation Of Ca Ix/xii As Anticancer Drug Targetsmentioning

confidence: 99%

Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment

et al. 2020

Self Cite

View full text Add to dashboard Cite

The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence the outcome of anticancer therapies. The biochemical rationale behind many of these phenomena resides in the activation of transcription factors such as hypoxia-inducible factor 1 and 2 (HIF-1/2). In turn, the HIF pathway activates a number of genes including those involved in glucose metabolism, angiogenesis, and pH regulation. Several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA IX and XII, actively participate in these processes and were validated as antitumor/antimetastatic drug targets. Here, we review the field of CA inhibitors (CAIs), which selectively inhibit the cancer-associated CA isoforms. Particular focus was on the identification of lead compounds and various inhibitor classes, and the measurement of CA inhibitory on-/off-target effects. In addition, the preclinical data that resulted in the identification of SLC-0111, a sulfonamide in Phase Ib/II clinical trials for the treatment of hypoxic, advanced solid tumors, are detailed.

show abstract

“…Ligands were docked with the standard precision mode (SP) of Glide 46e and the best 5 poses of each molecule retained as output. The best pose for each compound, evaluated in terms of coordination, hydrogen bond interactions and hydrophobic contacts, was refined with Prime 46d with a VSGB solvation model considering the target flexible within 3 Å around the ligand [47][48][49] .…”

Section: Computational Studiesmentioning

confidence: 99%

The antibiotic furagin and its derivatives are isoform-selective human carbonic anhydrase inhibitors

Pustenko

Nocentini

Gratteri

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

The clinically used antibiotic Furagin and its derivatives possess inhibitory activity on human (h) carbonic anhydrases (CA, EC 4.2.1.1), some of which are highly expressed in various tissues and malignancies (hCA IX/XII). Furagin exhibited good hCA IX and XII inhibition with K I s of 260 and 57 nM, respectively. It does not inhibit off-target CA I and poorly inhibited CA II (K I ¼ 9.6 lM). Some synthesised Furagin derivatives with aminohydantoin moieties as zinc binding group exhibited weak inhibition of CA I/II, and good inhibition of CA IX/XII with K I s ranging from 350 to 7400 and 150 to 5600 nM, respectively. Docking and molecular dynamics simulations suggest that selectivity for the cancer-associated CA IX/XII over CA II is due to strong H-bond interactions in CA IX/XII, involving the tail orientated towards hydrophobic area of the active site. These results suggest a possible drug repurposing of Furagin as anti-cancer agent.

show abstract

Steroids interfere with human carbonic anhydrase activity by using alternative binding mechanisms

Cited by 71 publications

References 37 publications

Synthesis, Computational Studies and Assessment of in Vitro Activity of Squalene Derivatives as Carbonic Anhydrase Inhibitors

Synthesis, Computational Studies and Assessment of in Vitro Activity of Squalene Derivatives as Carbonic Anhydrase Inhibitors

Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment

The antibiotic furagin and its derivatives are isoform-selective human carbonic anhydrase inhibitors

Contact Info

Product

Resources

About