Non-Experimental Search for Molecules With Antitumor Activity and Molecular Docking in the Series of Pyridinecarboxy Acid Derivatives

Abstract

Abstract. In the work, a pre-experimental screening of pyridinecarboxylic acid derivatives was performed by the PASS program, The work identified potential molecular targets for the implementation of the antitumor effect of a new domestic compound, an analogue of pyridine LHT-13-19. Using the "Autodock 4.2" software environment, flexible receptor-directed molecular biological docking was carried out in virtual reality, which makes it possible to most accurately predict the formation of a complex between a molecular structure and a biological target in real conditions of a specific biological system. For molecular docking, three-dimensional structures of the epidermal growth factor receptor (EGFR, PDB ID: 1M17, 4KN2) from the open electronic library Protein Data Bank (USA) were used. Molecules of compounds - pyridine derivatives LHT-13-19, LHT-16-19 and LHT-17-19 were synthesized in the Department of Chemistry, All-Union Research Center for Biological Active Compounds Safety (Russia). As a result of the experiments, it was found that all the studied molecules have inhibitory activity against proto-oncogenic kinases, however, in terms of the totality of predictive characteristics, as well as the likelihood of forming an antitumor effect, LHT-17-19, which was studied in docking studies, turned out to be the most promising compound. It was shown that LHT-17-19 has a high affinity for the epidermal growth factor kinase receptor EGFR-K, exhibits an affinity for the CSF1 receptor system, superior to that of all comparators - imatinib, erlotinib and pemetrexed. Also, in the process of docking approach and subsequent docking with the active site of tyrosine kinase EGFR-K and the human folate receptor FOLR2, an additional hydrogen bond is formed inside the LHT-17-19 molecule between the hydrogen proton of the amino group and the oxygen atom of the carbonyl group with atomic distances of 2.21 Å and 2 .49 Å, respectively.

An effective way for targeting EGFR-mediated carcinogenesis: an in vitro study

“…When performing docking studies, 9-ammonium-3,3dimethyl-3,4-dihydroacridine-1(2H)-OH showed high affinity for the EGFR kinase domain (PDB ID: 1M17) with a dG value of -7.9 kcal/mol, EDoc -5.45 kcal/mol and Ki 101.24 µM due to the formation of π-σ bonds between the aromatic nuclei of the 1,2,3,4tetrahydroacridine-1-OH fragment with the amino acid residues Leu820, Leu694 and Val702. In addition, the alkyl and π-alkyl complex is stabilized by the interactions of the methyl groups at position 3 and the 1,2,3,4tetrahydroacridine-1-OH fragment with the amino acid residues Lys721, Met742, Ala719, Leu820, and Val702 (Deryabina et al 2022).…”

“…In this work, we studied compound 9-aminium-3,3dimethyl-3,4-dihydroacridine-1(2H)-OH L-2-hydroxybutanediovate (laboratory number , obtained in the Department of Chemistry, Technology and Analytical Control of LLC "All-Russian Research Center for Biological Active Compounds Safety " (LLC "AURC BACS", Staraya Kupavna, Moscow region) and kindly provided by the head of the team of authors -Professor S.Ya. Skachilova (Kudryavtsev et al 2022).…”