Pharmacophore-Based Design of New Chemical Scaffolds as Translational Readthrough-Inducing Drugs (TRIDs)

Abstract

Translational readthrough-inducing drugs (TRIDs) rescue the functional full-length protein expression in genetic diseases, such as cystic fibrosis, caused by premature termination codons (PTCs). Small molecules have been developed as TRIDs to trick the ribosomal machinery during recognition of the PTC. Herein we report a computational study to identify new TRID scaffolds. A pharmacophore approach was carried out on compounds that showed readthrough activity. The pharmacophore model applied to screen different libraries containing more than 87000 compounds identified four hit-compounds presenting scaffolds with diversity from the oxadiazole lead. These compounds have been synthesized and tested using the Fluc reporter harboring the UGA PTC. Moreover, the cytotoxic effect and the expression of the CFTR protein were evaluated. These compounds, a benzimidazole derivative (NV2899), a benzoxazole derivative (NV2913), a thiazole derivative (NV2909), and a benzene-1,3-disulfonate derivative (NV2907), were shown to be potential new lead compounds as TRIDs, boosting further efforts to address the optimization of the chemical scaffolds.

Synthesis and Characterization of 2‐(2‐((1‐Aryl‐1H‐1,2,3‐triazol‐4‐yl)methoxy)phenyl)benzoxazoles: Evaluation of Cytotoxicity and Antioxidant Activity

“…In 13 CNMR spectrum, compound 6 j showed peaks at δ 156.88 ppm of C 2 carbon of benzoxazole ring, peak at δ 121.43 ppm was due to C 5 carbon of triazole ring and showed peak at δ 63.77 ppm due to methylene carbon. Overall, there were eight quaternary carbon signals.…”

“…[11][12] One of the four-hits identified as potential lead compound by pharmacophore-drug design of new chemical scaffold as translational readthrough-inducing drugs was a benzoxazole derivative (NV2913). [13] Nocarbenzoxazole F and nocarbenzoxazole G showed selective activities against HepG2 and HeLa cell lines [14,15] (Figure 1).…”

Deciphering the molecular mechanism of stop codon readthrough

“…3). The readthrough compounds (RTCs) RTC13, RTC14, RTC204, RTC219, GJ071, GJ072, NV2907, NV2909, NV2899 and NV2913 (Du et al ., 2009, 2013; Tutone et al ., 2020) (Table 2) have been identified and tested on different constructs and cell models of nonsense‐mutation‐related genetic diseases. In most cases, these molecules have shown a readthrough activity similar to that of ataluren or aminoglycosides such as gentamicin (G418) (Du et al ., 2009; Gomez‐Grau et al ., 2015; Tutone et al ., 2020).…”

In Silico Design, Synthesis, and Biological Evaluation of Anticancer Arylsulfonamide Endowed with Anti-Telomerase Activity

“…To the best of our knowledge, there is just one piece of evidence of arylsulfonamide derivatives (SEW05920) as an inhibitor of the TERT [45]. Exploiting our previous experience and outcomes in the use of computational approaches [46][47][48][49][50], we developed a structure-based computational approach to performing a virtual screening of an in-house arylsulfonamides library. Some arylsulfonamides have been identified as hits, also synthesized using green chemistry approaches and tested against three cancer cell lines K-562, HCT-116, and MCF-7.…”