Molecular Modeling of T. rangeli, T. brucei gambiense, and T. evansi Sialidases in Complex with the DANA Inhibitor

• Published in: Chemical biology & drug design 2012-07, Vol.80 (1), p.114-120
• Main Authors: Lima, Anderson H., Souza, Paulo R. M., Alencar, Nelson, Lameira, Jerônimo, Govender, Thavendran, Kruger, Hendrik G., Maguire, Glenn E. M., Alves, Cláudio N.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Binding Sites; Enzyme Inhibitors - chemistry; homology modeling; molecular dynamics; Molecular Dynamics Simulation; Molecular Sequence Data; N-Acetylneuraminic Acid - analogs & derivatives; N-Acetylneuraminic Acid - chemistry; Neuraminidase - antagonists & inhibitors; Neuraminidase - metabolism; Protein Structure, Tertiary; QM/MM; Quantum Theory; sialidases; Trypanosoma; Trypanosoma - enzymology; Trypanosoma brucei brucei - enzymology; Trypanosoma cruzi - enzymology
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/j.1747-0285.2012.01380.x

Trypanosomal (trans‐) sialidases are enzymes that catalyze the transfer of sialic acid residues between host and parasite glycoconjugates. Herein, we have used homology modeling to construct the 3D structures of sialidases from Trypanosoma brucei and Trypanosoma evansi. Hybrid quantum mechanical/molecular mechanical molecular dynamics simulations were used to determine the interaction energy between the 2‐Deoxy‐2,3‐didehydro‐N‐acetylneuraminic acid inhibitor and the three sialidases studied here. Our results suggest that the two constructed enzymes share the same basic fold motive of the Trypanosoma rangeli crystallographic structure. In addition, quantum mechanical/molecular mechanical molecular dynamics simulations show that the 2‐Deoxy‐2,3‐didehydro‐N‐acetylneuraminic acid inhibitor forms a stronger complex with Trypanosoma rangeli than with Trypanosoma brucei and Trypanosoma evansi sialidases. Finally, the interaction energy by residues shows that the arginine triad plays a decisive role to complex 2‐Deoxy‐2,3‐didehydro‐N‐acetylneuraminic acid with the enzyme through hydrogen bonding. Trypanosomal sialidases enzymes in complex with DANA inhibitor were investigated using homology modeling. Hybrid QM/MM and molecular dynamics simulations. The results suggest that sialidases share the same basic fold and arginine plays an important role to inhibitor–enzyme affinity.