Repositioning of experimentally validated anti-breast cancer peptides to target FAK-PAX complex to halt the breast cancer progression: a biomolecular simulation approach.

FAK (focal adhesin kinase), a tyrosine kinase, plays an imperative role in cell-cell communication, particularly in cell signaling systems. It is a multi-functional signaling protein, which integrates and transduces signals into cancer cells through growth factor receptors or integrin and its interaction with Paxillin (PAX). The molecular processes by which FAK promotes the development and progression of cancer have progressively established the possible relationship between FAK-PAX complex in many types of cancer. The interaction of FAX and PAX is very important in breast cancer and thus acts as an essential biomarker for drugs, vaccines or peptide inhibitor designing. In this regard, computational approaches, particularly peptide designing to target the binding interface of the interacting partners, would greatly assist the design of peptide inhibitors against various cancer. Accordingly, in this present study, we screened 236 experimentally validated anti-breast cancer peptides using computational drugs repositioning approach to design peptides targeting the FAK-PAX complex. Using protein-peptide docking the binding site for the HP1 was confirmed and a total of 236 anti-breast cancer peptides were screened. Among the 236, only 12 peptides reported a docking score better than the control. From these 12, Magainin with the docking score - 103.8 ± 10.3 kcal/mol, NRC-07 with the docking score - 100.8 ± 16.5 kcal/mol, and Indolicidin with the docking score - 101.7 ± 3.9 kcal/mol, peptides potentially inhibit the FAX-PAX binding. Calculation of protein's motion and FEL revealed the binding and inhibitory behavior. Moreover, binding free energy (MM/GBSA) confirmed that Magainin exhibited the total binding energy - 53.28 kcal/mol, NRC-07 possessed the TBE - 44.16 kcal/mol, and Indolicidin reported the TBE of - 40.48 kcal/mol, thus explaining the inhibitory potential of these peptides. In conclusion, these peptides exhibit strong inhibitory potential and could abrogate the FAK-PAX complex in in vitro models and thus may relieve the burden of breast cancer.

Evaluation of the Whole Proteome of Achromobacter xylosoxidans to Identify Vaccine Targets for mRNA and Peptides-Based Vaccine Designing Against the Emerging Respiratory and Lung Cancer-Causing Bacteria.

Achromobacter xylosoxidans is a rod-shaped Gram-negative bacterium linked with causing several infections which mostly includes hematological malignancies. It has been recently reported to be associated with the development and progression of lung cancer and is an emerging respiratory disease-causing bacterium. The treatment of individuals infected with A. xylosoxidans bacteremia is difficult due to the fact that this pathogen has both intrinsic and acquired resistance mechanisms, typically resulting in a phenotype of multidrug resistance (MDR). Efforts are needed to design effective therapeutic strategies to curtail the emergence of this bacterium. Computational vaccine designing has proven its effectiveness, specificity, safety, and stability compared to conventional approaches of vaccine development. Therefore, the whole proteome of A. xylosoxidans was screened for the characterization of potential vaccine targets through subtractive proteomics pipeline for therapeutics design. Annotation of the whole proteome confirmed the three immunogenic vaccine targets, such as (E3HHR6), (E3HH04), and (E3HWA2), which were used to map the putative immune epitopes. The shortlisted epitopes, specific against Cytotoxic T Lymphocytes, Helper T-cell Lymphocytes, and linear B-Cell, were used to design the mRNA and multi-epitopes vaccine (MEVC). Initial validations confirmed the antigenic and non-allergenic properties of these constructs, followed by docking with the immune receptor, TLR-5, which resulted in robust interactions. The interaction pattern that followed in the docking complex included formation of 5 hydrogen bonds, 2 salt bridges, and 165 non-bonded contacts. This stronger binding affinity was also assessed through using the mmGBSA approach, showing a total of free binding energy of -34.64 kcal/mol. Further validations based on in silico cloning revealed a CAI score of 0.98 and an optimal percentage of GC contents (54.4%) indicated a putatively higher expression of the vaccine construct in Escherichia coli. Moreover, immune simulation revealed strong antibodies production upon the injection of the designed MEVC that resulted in the highest peaks of IgM+ IgG production (>3,500) between 10 and 15 days. In conclusion the current study provide basis for vaccine designing against the emerging A. xylosoxidans, which demands further experimental studies for in vitro and in vivo validations.