Investigation of the Molecular Interactions of Vaccine Adjuvants: Can a Strategic Trio of Toll-like Receptor Agonists Enhance Efficacy in a Multifaceted Approach?

Abstract

Background: The imperative need for effective vaccines against viral diseases has intensified research on adjuvants to enhance immune responses. Toll-like receptor (TLR) agonists, such as Imiquimod, Resiquimod, and CpG oligodeoxynucleotides (CpG ODN), are some crucial components in vaccine formulations. This study investigated the molecular interactions and binding affinities of TLR4, TLR7/8, and TLR9 agonists, through in silico techniques. Methods: The three-dimensional structure of human TLR9 was predicted using Iterative Threading ASSEmbly Refinement. Homology modeling was employed using a multi-step approach to generate the human TLR9 model including template identification, ab initio modeling, iterative refinement, and final model generation of the crystallographic structure. Molecular docking and simulation studies were performed using AutoDock Vina, HDOCK, and GROningen MAchine for Chemical Simulations tools. The molecular docking study revealed binding sites and binding affinities of adjuvants in the binding regions of target TLRs. Molecular dynamics simulations and Molecular Mechanics/Poisson-Boltzmann Surface Area calculations ascertain the stability and binding energies of the TLR-adjuvant complexes. Results: Results indicate distinct interactions, with Resiquimod showing superior affinity toward TLR7. QS21, on the other hand, emerged as a potent TLR4 agonist, while CpG ODN 2006 binds specifically to TLR9. The study proposes a strategic combination of QS21, Resiquimod, and CpG ODN 2006 as a potential adjuvant system, offering a multifaceted approach to enhance vaccine efficacy. Conclusions: This study furnishes preliminary data and establishes the foundational framework for subsequent inquiries encompassing both in vitro and in vivo studies concerning vaccine adjuvant systems.