An in silico Study of Benzophenone Derivatives as Potential Non-Competitive Inhibitors of Trypanosoma cruzi and Leishmania Amazonensis Cysteine Proteinases

Abstract

This study investigates the mechanisms of interaction between benzophenone derivatives and cruzain and Llacys1 (the protein expressed by cysteine protease gene isoform 1 of L. amazonensis) by homology modelling, docking and molecular dynamics simulation. The results predict that the same binding site in cruzain and Llacys1 is involved in complexes with benzophenone derivatives that cause non-competitive inhibition of the enzymes. The Gln residue is conserved among the enzymes, and is shown to be a key residue in the allosteric site of these cysteine proteases and in the interaction with benzophenone derivatives. The binding free energies highlight that the main energetic term contributing to the cruzain-and Llacys1-benzophenone compound interactions is the van der Waals term. Experimental results showed that benzophenone derivatives are promising potential inhibitors of cysteine proteases. Moreover, we found that two benzophenone derivatives are the most effective inhibitors of cruzain and L. amazonensis cysteine protease.

Novel chemical scaffold as potential drug against Leishmania donovani: Integrated computational and experimental approaches

“…The binding and active site region is very compact and rigid, and stable in the dynamic environment, as evidenced by the RMSF value of the residues implicated in the active and binding site region being less than 0.4 nm and the reduced fluctuation observed in all protein‐ligand complexes 7 . In an MD simulation, the protein complex's compactness and fluctuation are depicted by the radius of gyration 7,40 . This analysis demonstrates the folding and unfolding of polypeptide chains or the various protein conformations 41 .…”

“…A few key residues, i.e., Tyr238, His242, and His245 found which were commonly involved in hydrogen bond formation between ligand and binding site residue of Ld citrate synthase protein in both docking and MD Simulation. The molecular mechanics Poisson–Boltzmann surface area (MM‐PBSA), besides MD simulation, is one of the most widely used methods for calculation of binding affinities and also the rescoring of the docked complexes, which help in the selection of the best drug molecule 40 . In the calculation of free binding energy, four individual energy components were involved.…”

“…Based on RMSD, RMSF, Radius of gyration, and hydrogen bond analysis, MD simulation investigations were carried out. Protein‐ligand complexes’ structural stability, lack of fluctuation in their catalytic area, and compactness demonstrated that these ligands would interact with proteins in a stable and robust manner at their binding sites 7,39,40 . All ligands had formed hydrogen bonds, but Amyral had formed the highest seven hydrogen bonds with a continuity of four hydrogen bonds.…”

ACW-02 an Acridine Triazolidine Derivative Presents Antileishmanial Activity Mediated by DNA Interaction and Immunomodulation

“…Because there is no crystallographic structure of the cysteine protease B from Leishmania amazonensis (CPBla), it was decided to carry out a homology modeling and thus build the model similar to other works [ 90 , 91 ]. Initially, the amino acid sequence for the required cysteine protease was obtained from the National Center for Biotechnology Information Search database (NCBI, ( , accessed on 10 September 2022) [ 92 ], under the code AAP21894, consisting of 353 amino acids.…”

Discovery of Non-Peptidic Compounds against Chagas Disease Applying Pharmacophore Guided Molecular Modelling Approaches

“…Cysteine proteases often called as Cruzain [21,22] and sometimes referred to as cruzipian [23,24,25] illuminates to be a promising target for identifying new drugs. This belongs to the C1 protein family and is expressed at all the stages of T. cruzi playing an important role in cell invasion, immune invasion, intracellular multiplication and differentiation [4,26,27,28,29].…”