Quantitative structure-activity relationship of the thymidylate synthase inhibitors of Mus musculus in the series of quinazolin-4-one and quinazolin-4-imine derivatives

Veronika R Khairullina; Alfiya R Gimadieva; Anatoly Ya Gerchikov; Akhat G Mustafin; Felix S Zarudii

doi:10.1016/j.jmgm.2018.09.002

Quantitative structure-activity relationship of the thymidylate synthase inhibitors of Mus musculus in the series of quinazolin-4-one and quinazolin-4-imine derivatives

J Mol Graph Model. 2018 Oct:85:198-211. doi: 10.1016/j.jmgm.2018.09.002. Epub 2018 Sep 10.

Authors

Veronika R Khairullina¹, Alfiya R Gimadieva², Anatoly Ya Gerchikov³, Akhat G Mustafin⁴, Felix S Zarudii⁵

Affiliations

¹ Bashkir State University, 32 Z. Validi str., Ufa, 450076, Russian Federation. Electronic address: KhVerRad@gmail.com.
² Ufa Institute of Chemistry - Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences, 71 prospect Oktyabrya, Ufa, 450054, Russian Federation.
³ Bashkir State University, 32 Z. Validi str., Ufa, 450076, Russian Federation.
⁴ Bashkir State University, 32 Z. Validi str., Ufa, 450076, Russian Federation; Ufa Institute of Chemistry - Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences, 71 prospect Oktyabrya, Ufa, 450054, Russian Federation.
⁵ Bashkir State Medical University, 3 Lenina str, Ufa, 450000, Russian Federation.

PMID: 30227365
DOI: 10.1016/j.jmgm.2018.09.002

Abstract

A quantitative structure-activity relationship analysis of the 2-methylquinazolin-4-one and quinazolin-4-imine derivatives, well-known antifolate thymidylate synthase (TYMS) inhibitors, has been performed in the range IC₅₀ = 0.4÷380000.0 nmoL/L using the GUSAR 2013 program. Based on the MNA and QNA descriptors using the self-consistent regression, 6 statistically significant consensus models for predicting the IC₅₀ numerical values have been constructed. These models demonstrate high and moderate prognostic accuracies for the training and external validation test sets, respectively. The molecular fragments of TYMS inhibitors regulating their antitumor activity are identified. The obtained data open opportunities for developing novel promising inhibitors of TYMS.

Keywords: Antifolate thymidylate synthase inhibitors; GUSAR 2013; QNA and MNA descriptors; QSAR models; Structure–activity relationships.

MeSH terms

Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Models, Molecular*
Molecular Conformation*
Molecular Structure
Quantitative Structure-Activity Relationship*
Quinazolinones / chemistry*
Quinazolinones / pharmacology
Thymidylate Synthase / antagonists & inhibitors
Thymidylate Synthase / chemistry*

Substances

Enzyme Inhibitors
Quinazolinones
4-hydroxyquinazoline
Thymidylate Synthase