In Silico Structure-Activity Relationship and Virtual Screening of Monosubstituted Doxycycline with Pseudomonas Aeruginosa Lipase

Doxycycline(4,5,5,6,12)-4-(dimethylamino)-3,5,10,12,12-pentahydroxy-6-methyl1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene2-carboxamide) is a drug used for the treatment of infections caused by bacteria and protozoa. We carried out molecular docking for six analogous structurally diverse (doxycycline) against Pseudomonas aeruginosa lipase using Patchdock and Firedock softwares server. Extensive structure activity relationship work was carried out with these molecules. Physicochemical, lipophilicity, solubility, pharmacokinetics and Lipinski druglikeness of doxycycline and its analogues were evaluated. These molecules were designed by substituting NH2 with NO2, CONH2, COOH, CHO and OCH3 functional groups. The scoring function (empirical binding free energy) was used to estimate the inhibitory activity of protein-ligand complex. The binding energy of doxycycline was -39.25kcal/ mol. The free binding energies of NO2, CHO, CONH2, COOH, and OCH3 analogues of doxycycline were -43.43, -43.86, -44.97, -39.40 and -35.78Kcal/mol respectively. All the monosubstituted analogues of doxycycline, except COOH monosubstituted analogue showed lower values than the non substituted doxycycline. These lower values (more negative values), means that they show better antimicrobial activity than doxycycline. These results clearly indicated that the new substituents may be better antimicrobial agents. Synthesis and pre-clinical studies of these monosubstituted derivatives with Pseudomonas aeruginosa lipase is recommended in order to confirm their new potentials as better antimicrobial agent than the unsubstituted analogue.