MOLECULAR DYNAMICS SIMULATION OF FOUR BIFLAVONOIDS WITH THE LEISHMANOLYSIN (gp63) PROTEIN OF Leishmania major

AbstractLeishmanolisyn (gp63) is a 63 kDa surface metalloprotease belonging to the M8 family (subclan MA (M), metzincines) that is found in both promastigote and amastigote ofleishmania ssp. It constitutes one of the virulence factors in the pathogenesis of Leishmania spp., being crucial in its entry into the macrophage and in complement activation. Therefore, gp63 may be a therapeutic alternative for potential new drugs needed to combat this disease. Among the many functional groups of naturally occurring compounds, the biflavonoids amentoflavone (A), lanaraflavone (L), podocarpusflavone A (PA), and podocarpusflovone B (PB) are promising candidate ligands for the treatment of all forms of leishmaniasis. In this study we carried out the validated molecular dynamics simulation with GROMACS, using mean square deviation (RMSD), mean square fluctuation (RMSF), the radius of gyration (Rg), and intermolecular hydrogen bonds (H-bonds) between the gp63 protein ofL. major(1LML) in complex with the four biflavonoids. In addition, the free binding energies were estimated using the MM-PBSA method, to determine their stability in the active site of the protein. The computational analysis revealed that the interaction of lanaroflavone (ΔGBing= -156.75 ± 31.91 Kcal/mol forL. major) remained stable in this enzyme, revealing their remarkable potential as a possible antileishmanial agent to combat the Leishmania parasite. On the other hand, amentoflavone, podocarpusflavone A, and B also showed a good affinity for both metalloproteases according to the ΔGbindvalues obtained.