A Mechanistic Probe into the Dual Inhibition of T. cruzi Glucokinase and Hexokinase in Chagas Disease Treatment - A Stone Killing Two Birds?

Glucokinase (GLK) and Hexokinase (HK) have been characterized as essential targets in Trypanosoma cruzi (Tc)-mediated infection. A recent study reported the propensity of the concomitant inhibition of TcGLK and TcHK by compounds GLK2-003 and GLK2-004, thereby presenting an efficient approach in Chagas disease treatment. We investigated this possibility using atomic and molecular scaling methods. Sequence alignment of TcGLK and TcHK revealed that both proteins shared approximately 33.3 % homology in their glucose/inhibitor binding sites. The total binding free energies of GLK2-003 and GLK2-004 were favorable in both proteins. PRO92 and THR185 were pivotal to the binding and stabilization of the ligands in TcGLK, likewise their conserved counterparts, PRO163 and THR237 in TcHK. Both compounds also induced a similar pattern of perturbations in both TcGLK and TcHK secondary structure. Findings from this study therefore provide insights into the underlying mechanisms of dual inhibition exhibited by the compounds. These results can pave way to discover and optimize novel dual Tc inhibitors with favorable pharmacokinetics properties eventuating in the mitigation of Chagas disease.

Covalent simulations of covalent/irreversible enzyme inhibition in drug discovery: a reliable technical protocol.

AIM: Irreversible covalent inhibition of biological targets in disease pathogenesis is an emerging field in drug design. Computational techniques have assumed a critical role in understanding covalent enzyme inhibition. However, a gap currently exists with regards to the reliability and reproducibility of currently available protocols available in literature and open scientific forums. METHODOLOGY/RESULTS: Appropriate ligand and protein target are selected, docked covalently or noncovalently using respective docking tools. Both components are subjected to premolecular dynamic preparations. This was followed by parameterization of the ligand, protein and covalent complex, respectively. The production runs were initiated and the resulting trajectories are saved and analyzed. CONCLUSION: This protocol is reliable and reproducible, hence would advance the development of irreversible covalent inhibitors toward disease treatment.