Management of pharmaceutical ICH M7 (Q)SAR predictions – The impact of model updates

Hasselgren, Catrin; Bercu, Joel P.; Cayley, Alex; Cross, Kevin P.; Glowienke, Susanne; Kruhlak, Naomi L.; Muster, Wolfgang; Nicolette, John; Reddy, M. Vijayaraj; Saiakhov, Roustem; Dobo, Krista L.

doi:10.1016/j.yrtph.2020.104807

Cited by 21 publications

(3 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In these cases, the Q(SAR) approach is of vital importance. (Q)SAR models make predictions of biological activity based on structural components [37]. This approach is vital during the early stages of searching for potentially active drug substances.…”

Section: Genotoxicitymentioning

confidence: 99%

New Charged Cholinesterase Inhibitors: Design, Synthesis, and Characterization

Mlakić,

Barić,

Ratković

et al. 2024

Molecules

View full text Add to dashboard Cite

Triazoles and triazolium salts are very common subunits in the structures of various drugs. Medicaments with a characteristic 1,2,3-triazole core are also being developed to treat neurodegenerative disorders associated with cholinesterase enzyme activity. Several naphtho- and thienobenzo-triazoles from our previous research emerged as being particularly promising in that sense. For this reason, in this research, new naphtho- and thienobenzo-triazoles 23–34, as well as 1,2,3-triazolium salts 44–51, were synthesized and tested. Triazolium salts 44–46 showed excellent activity while salts 47 and 49 showed very good inhibition toward both butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) enzymes. In contrast, neutral photoproducts were shown to be selective towards BChE but with very good inhibition potential as molecules 24–27. The representative of newly prepared compounds, 45 and 50, were stable in aqueous solution and revealed intriguing fluorimetric properties, characterized by a strong Stokes shift of >160 nm. Despite their condensed polycyclic structure shaped similarly to well-known DNA-intercalator ethidium bromide, the studied compounds did not show any interaction with ds-DNA, likely due to the unfavorable steric hindrance of substituents. However, the studied dyes bind proteins, particularly showing very diverse inhibition properties toward AChE and BChE. In contrast, neutral photoproducts were shown to be selective towards a certain enzyme but with moderate inhibition potential. The molecular docking of the best-performing candidates to cholinesterases’ active sites identified cation–π interactions as the most responsible for the stability of the enzyme–ligand complexes. As genotoxicity studies are crucial when developing new active substances and finished drug forms, in silico studies for all the compounds synthesized have been performed.

show abstract

Section: Genotoxicitymentioning

confidence: 99%

New Charged Cholinesterase Inhibitors: Design, Synthesis, and Characterization

Mlakić,

Barić,

Ratković

et al. 2024

Molecules

View full text Add to dashboard Cite

show abstract

“…In these cases, the Q(SAR) approach is of vital importance. (Q)SAR models make predictions of biological activity based on structural components [55]. (Q)SAR models are especially vital during the early stages of searching for potentially active drug substances.…”

Section: Genotoxicity Of 1-14mentioning

confidence: 99%

Cholinesterase Inhibition and Antioxidative Capacity of New Heteroaromatic Resveratrol Analogs: Synthesis and Physico-Chemical Properties

Mlakić,

Odak,

Barić

et al. 2024

Preprint

View full text Add to dashboard Cite

The targeted compounds in this research, resveratrol analogs 1–14 were synthesized as mixtures of isomers by the Wittig reaction using heterocyclic triphenylphosphonium salts and various benzaldehydes. The planned compounds were those possessing the trans-configuration as the biologically active trans-resveratrol. The pure isomers were obtained by repeated column chromatography in various isolated yields depending on the heteroaromatic ring. It was found that butyrylcholinesterase (BChE) was more sensitive to the heteroaromatic resveratrol analogs than acetylcholinesterase (AChE), except for 6, the methylated thiophene derivative with chlorine, which showed equal inhibition toward both enzymes. Compounds 5 and 8 achieved the highest BChE inhibition with IC50 values of 22.9 and 24.8 μM, respectively. The same as with AChE and BChE, methylated thiophene subunits of resveratrol analogs showed better enzyme inhibition than unmethylated ones. Two antioxidant spectrophotometric methods, DPPH and CUPRAC, were applied to determine the antioxidant potential of new heteroaromatic resveratrol analogs. Molecular docking of these compounds was conducted to visualize the ligand-active site complexes' structure and identify the non-covalent interactions responsible for the complex's stability, which influence the inhibitory potential. As ADME properties are crucial in developing drug product formulations, they have also been addressed in this work. The potential genotoxicity is evaluated by in silico studies for all compounds synthesized.

show abstract

“…ICH M7 recommends that bacterial mutagenicity should be assessed using two QSAR methodologies, namely, by expert rule-based and statistics-based methodologies. The prediction accuracy of QSAR tools is improved by increasing the number of training sets and modifying algorithms [ 2 , 3 ]. However, the mutagenicity of several structures, such as aromatic amines, is still difficult to predict when using QSAR tools [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

A local QSAR model based on the stability of nitrenium ions to support the ICH M7 expert review on the mutagenicity of primary aromatic amines

Furukawa¹,

Ono²,

Yamada³

et al. 2022

Genes and Environ

View full text Add to dashboard Cite

Background Aromatic amines, often used as intermediates for pharmaceutical synthesis, may be mutagenic and therefore pose a challenge as metabolites or impurities in drug development. However, predicting the mutagenicity of aromatic amines using commercially available, quantitative structure–activity relationship (QSAR) tools is difficult and often requires expert review. In this study, we developed a shareable QSAR tool based on nitrenium ion stability. Results The evaluation using in-house aromatic amine intermediates revealed that our model has prediction accuracy of aromatic amine mutagenicity comparable to that of commercial QSAR tools. The effect of changing the number and position of substituents on the mutagenicity of aromatic amines was successfully explained by the change in the nitrenium ion stability. Furthermore, case studies showed that our QSAR tool can support the expert review with quantitative indicators. Conclusions This local QSAR tool will be useful as a quantitative support tool to explain the substituent effects on the mutagenicity of primary aromatic amines. By further refinement through method sharing and standardization, our tool can support the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M7 expert review with quantitative indicators.

show abstract

Management of pharmaceutical ICH M7 (Q)SAR predictions – The impact of model updates

Cited by 21 publications

References 31 publications

New Charged Cholinesterase Inhibitors: Design, Synthesis, and Characterization

New Charged Cholinesterase Inhibitors: Design, Synthesis, and Characterization

Cholinesterase Inhibition and Antioxidative Capacity of New Heteroaromatic Resveratrol Analogs: Synthesis and Physico-Chemical Properties

A local QSAR model based on the stability of nitrenium ions to support the ICH M7 expert review on the mutagenicity of primary aromatic amines

Contact Info

Product

Resources

About