Abetting host immune response by inhibiting rhipicephalus sanguineus Evasin-1: An in silico approach

Abstract

The brown dog tick (Rhipicephalus sanguineus) is the most prevalent tick in the world and a well-recognized vector of many pathogens affecting dogs and occasionally humans. Pathogens exploit tick salivary molecules for their survival and multiplication in the vector and transmission to and establishment in the hosts. Tick saliva contains various non-proteinaceous substances and secreted proteins that are differentially produced during feeding and comprise of inhibitors of blood congealing and platelet aggregation, vasodilatory and immunomodulatory substances, and compounds preventing itch and pain. One of these proteins is Evasin-1, which has a high binding affinity to certain types of chemokines. The binding of Evasin-1 to chemokines prevents the detection and immune response of the host to R. sanguineus, which may result in the successful transmission of pathogens. In this study, we screened potential Evasin-1 inhibitor based on the pharmacophore model derived from the binding site residues. Hit ligands were further screened via molecular docking and virtual ADMET prediction, which resulted in ZINC8856727 as the top ligand (binding affinity: -9.1 kcal/mol). Molecular dynamics simulation studies, coupled with MM-GBSA calculations and principal component analysis revealed that ZINC8856727 plays a vital role in the stability of Evasin-1. We recommend continuing the study by developing a formulation that serves as a potential medicine aid immune response during R. sanguineus infestation.

Curcumin and Plumbagin Synergistically Target the PI3K/Akt/mTOR Pathway: A Prospective Role in Cancer Treatment

“…On the other hand, the Cα-backbone of the target protein bound to curcumin (PI3K-C) showed a deviation of 3.9 Å. Interestingly, the consortia of plumbagin and curcumin bound to PI3K protein (PI3K-C-P) exhibited a very stable RMSD of 2.3 Å. A stable RMSD plot during simulation signifies good convergence and stable conformations [ 23 , 25 , 26 , 27 ]. Therefore, it can be suggested that PI3K forms a quite stable complex when subjected to synergistic binding with plumbagin and curcumin.…”

“…The increased flexibility of the residues conformed into the loop region may be the cause of high residual fluctuations, whereas the lower fluctuation of the other residues throughout the course of 100 ns simulation suggests rigid amino acid conformations ( Figure 5 B). Therefore, it can be inferred from RMSF plots that the proteins have rigid structures during simulation in ligand-bound conformations [ 26 , 27 ]. In this study, the radius of gyration Rg (which denotes the compactness of a protein) values of the protein C-backbone of the PI3K-P complex increased from 19.9 to 20.0 Å, but the Rg values of the PI3K-C complex decreased from 19.9 to 19.3 Å ( Figure 5 C).…”

“…The higher residual fluctuations signify higher flexibility of the residues in the loop region, while the less-fluctuating residues indicate the rigid amino acid conformations during the simulation time ( Figure 6 B). Therefore, the RMSF plots of Akt interaction with the combination of ligands suggest a rigid protein conformation during the course of the simulation [ 26 , 27 ]. Furthermore, the compactness of the Akt protein was evaluated by measuring the Rg value.…”

“…The complex mTOR-C-P formed when both curcumin and plumbagin were bound to the mTOR protein and had an RMSD of 2.0 Å. The lowering of RMSD in the mTOR-C-P indicates good convergence and stable conformation of the complex [ 25 , 26 , 27 ]. The RMSF plot showed considerable spikes of fluctuation in Cα-atoms of mTOR-P and mTOR-C complexes, whereas no substantial spikes were observed in the mTOR-C-P complex.…”

Computational Studies to Identify Potential Inhibitors Targeting the DprE1 Protein in Mycobacterium tuberculosis

“…The concentration of the salts was kept at 0.15 M sodium and chloride ions expectedly to mimic the physiological conditions. 40,41 Desmond was performed in an NPT ensemble for corresponding time intervals of 70ns to 100ns at temperature 300k and pressure of 1.70 bar. 42…”