Trypanocidal Mechanism of Action and in silico Studies of p-Coumaric Acid Derivatives

Abstract

Trypanosoma species are responsible for chronic and systemic infections in millions of people around the world, compromising life quality, and family and government budgets. This group of diseases is classified as neglected and causes thousands of deaths each year. In the present study, the trypanocidal effect of a set of 12 ester derivatives of the p-coumaric acid was tested. Of the test derivatives, pentyl p-coumarate (7) (5.16 ± 1.28 μM; 61.63 ± 28.59 μM) presented the best respective trypanocidal activities against both epimastigote and trypomastigote forms. Flow cytometry analysis revealed an increase in the percentage of 7-AAD labeled cells, an increase in reactive oxygen species, and a loss of mitochondrial membrane potential; indicating cell death by necrosis. This mechanism was confirmed by scanning electron microscopy, noting the loss of cellular integrity. Molecular docking data indicated that of the chemical compounds tested, compound 7 potentially acts through two mechanisms of action, whether by links with aldo-keto reductases (AKR) or by comprising cruzain (CZ) which is one of the key Trypanosoma cruzi development enzymes. The results indicate that for both enzymes, van der Waals interactions between ligand and receptors favor binding and hydrophobic interactions with the phenolic and aliphatic parts of the ligand. The study demonstrates that p-coumarate derivatives are promising molecules for developing new prototypes with antiprotozoal activity.

Bioactivity and Molecular Docking Studies of Derivatives from Cinnamic and Benzoic Acids

“…The OMEGA software [41] was used to obtain the initial 3D structure of compound 7, and AM1-BCC charges were added to it with MOLCHARGE [42]. Molecular docking of compound 7 to its potential targets was performed with Gold [43] following the same procedure as in our previous research [44,45]. Water molecules, cocrystalized ligands, and cofactors not involved in ligand binding were removed from the receptors.…”

“…Calculations. All molecular dynamics (MD) simulations and free energy of binding calculations were performed with Amber 2018 [14] following the procedure of our previous publication [45]. All complexes were subject to the same modeling procedure which included two minimization steps, the heating of the systems, their equilibration, production runs, the extraction of representative snapshots, and the estimation of the free energies of binding from them through MM-PBSA calculations.…”

Drugs Repurposing Using QSAR, Docking and Molecular Dynamics for Possible Inhibitors of the SARS-CoV-2 Mpro Protease

“…One initial 3D conformer of each compound was generated with OpenEye's Omega [54] (available: http://www.eyesopen.com) and partial atomic charges were added to them with Molcharge from OpenEye. Docking was performed as described in previous publications [55] by using the Gold software [56]. The binding site was defined from the inhibitor co-crystalized with M pro and the residues forming it were considered as flexible during calculations.…”

“…The selection of the most probable binding modes of each compound to M pro was carried out following the previously described consensus scoring methodology [55,57,58]. Consensus scoring took place independently for each compound to rank its 30 predicted binding modes.…”

“…This was achieved by means of a home-made python script in two steps: (1) superimposition of the binding pocket containing the docked ligand into the one not explored during docking calculations, and (2) the extrapolation of the ligand and side chains conformers coordinates to the ligand free active site. MD simulations of these dimeric complexes proceeded with Amber 18 [59] as previously described [55,58].…”