Affiliation:
1. I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation,
2. Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation,
3. N.P. Ogarev National Research Mordovia State University, Saransk, Russian Federation,
Abstract
In this work, the molecular targets of a new compound with antitumor effect, a 9-dihydroacridone derivative, were determined. The study was carried out in a virtual software environment for receptor-oriented flexible docking Autodock 4.2. The ligands were prepared using the MGL Tools 1.5.6. Ligand optimization was performed using the Avogadro software. The crystallographic structures of the active site macromolecules of human folate receptors (FOLR2) and colony stimulating factor kinase 1 (CSF1R) from the Protein Data Bank (PDB ID: 4KN2 and 4R7I, respectively) were used. A new compound, 9-aminium-3,3-dimethyl-3,4-dihydroacridin-1(2Н)-one L-2-hydroxybutanediovatate (laboratory name LHT-17-19), was studied. LHT-17-19 formed a stable complex with the type III receptor of tyrosine kinase of the monocyte and macrophage colony-stimulating factor (CSF1R) and with the folate receptor FOLR2 with Affinity DG -10.2 kcal/M, EDoc -6.82 kcal/M, Ki 9.99 uM and 10.0 kcal/ M, Edoc -7.05 kcal/M, Ki 6.85 uM, respectively. In terms of the main indicators of affinity LHT-17-19 was not inferior to the reference drugs imatinib and pemetrexed. Receptor kinases CSF1R and FOLR2 can be considered as potential molecular targets for novel medication candidate 9-aminium-3,3-dimethyl-3,4-dihydroacridin-1(2H)-one L-2-hydroxybutanediovate.