| Autor: |
Kovalishyn V; V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, Kyiv, Ukraine., Severin O; V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, Kyiv, Ukraine., Kachaeva M; V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, Kyiv, Ukraine., Semenyuta I; V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, Kyiv, Ukraine., Keith KA; Department of Pediatrics, Division of Pediatric Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA., Harden EA; Department of Pediatrics, Division of Pediatric Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA., Hartline CB; Department of Pediatrics, Division of Pediatric Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA., James SH; Department of Pediatrics, Division of Pediatric Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA., Metelytsia L; V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, Kyiv, Ukraine., Brovarets V; V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, Kyiv, Ukraine. |
| Abstrakt: |
QSAR studies of a set of previously synthesized azole derivatives tested against human cytomegalovirus (HCMV) were performed using the OCHEM web platform. The predictive ability of the classification models has a balanced accuracy (BA) of 73-79%. The validation of the models using an external test set proved that the models can be used to predict the activity of newly designed compounds with a reasonable accuracy within the applicability domain (BA = 76-83%). The models were applied to screen a virtual chemical library with expected activity of compounds against HCMV. The five most promising new compounds were identified, synthesized and their antiviral activities against HCMV were evaluated in vitro. Two of them showed some activity against the HCMV strain AD169. According to the results of docking analysis, the most promising biotarget associated with HCMV is DNA polymerase. The docking of the most active compounds 1 and 5 in the DNA polymerase active site shows calculated binding energies of -8.6 and -7.8 kcal/mol, respectively. The ligand's complexation was stabilized by the formation of hydrogen bonds and hydrophobic interactions with amino acids Lys60, Leu43, Ile49, Pro77, Asp134, Ile135, Val136, Thr62 and Arg137. |
