Conventional de novo drug design is time consuming, laborious, and resource intensive. In recent years, emerging in silico approaches have been proven to be critical to accelerate the process of bringing drugs to market. Molecular dynamics (MD) simulations of single molecule and molecular complexes have been commonly applied to achieve accurate binding modes and binding energies of drug-receptor interactions. A derivative of MD, namely, steered molecular dynamics (SMD), has been demonstrated as a promising tool for rational drug design. In this paper, we review various studies over the last 20 years using SMD simulations, thus paving the way to determine the relationship between protein structure and function. In addition, the paper highlights the use of SMD simulation for in silico drug design. We also aim to establish an understanding on the key interactions which play a crucial role in the stabilization of peptide-ligand interfaces, the binding and unbinding mechanism of the ligand-protein complex, the mechanism of ligand translocating via membrane, and the ranking of different ligands on receptors as therapeutic candidates.

Influenza A has caused several deadly pandemics throughout human history. The virus is often resistant to developed treatments because of its genetic drift or shift property. Broad-spectrum antibodies show a promising potential to overcome the resistance of influenza viruses. In silico studies on broad-reactive antibodies and their interactions with hemagglutinins might shed light on the rational design of a universal vaccine. In this study, 11 broad-spectrum antibodies (or antigen-binding fragments) and 14 hemagglutinins of H3N2 and H5N1 strains were docked and analyzed to provide information about the construction of the scaffold for using universal antibodies against the influenza A virus. Antigen-binding fragments that have high number of appearances in the top 3 within each H3 and H5 subtypes were chosen for protein-protein interaction analysis. The results show that while the hydrogen bond is important for Ab/Fab binding to H3, the H5-Ab/Fab system may need cation-pi interaction for a strong interaction.

Influenza virus A is a significant agent involved in the outbreak of worldwide epidemics, causing millions of fatalities around the world by respiratory diseases and seasonal illness. Many projects had been conducting to investigate recovered infected patients for therapeutic vaccines that have broad-spectrum activity. With the aid of the computational approach in biology, the designation for a vaccine model is more accessible. We developed an in silico protocol called iBRAB to design a broad-reactive Fab on a wide range of influenza A virus. The Fab model was constructed based on sequences and structures of available broad-spectrum Abs or Fabs against a wide range of H1N1 influenza A virus. As a result, the proposed Fab model followed iBRAB has good binding affinity over 27 selected HA of different strains of H1 influenza A virus, including wild-type and mutated ones. The examination also took by computational tools to fasten the procedure. This protocol could be applied for a fast-designed therapeutic vaccine against different types of threats.

Hand, foot, and mouth disease (HFMD) is a common infection that primarily affects children in preschool and kindergarten; however, there is yet no vaccination or therapy available. Despite the fact that current research is only focused on numerous strains of Enterovirus—A71 (EV-A71) 3C protease (3Cpro), these investigations are entirely separate and unrelated. Antiviral agents must therefore be tested on several EV strains or mutations. In total, 21 previously reported inhibitors were evaluated for inhibitory effects on eight EV-A71 3Cpro, including wild-type and mutant proteins in this study, and another 29 powerful candidates with inhibitory effects on EV-A71 were investigated using the molecular docking approach. This method is to determine the broad-spectrum of the antiviral agents on a range of strains or mutants because the virus frequently has mutations. Even though Rupintrivir is reported to pass phase I clinical trial, 4-iminooxazolidin-2-one moiety (FIOMC) was shown to have a broader anti-3Cpro spectrum than Rupintrivir. Meanwhile, Hesperidin possessed a better 3Cpro inhibitory capability than FIOMC. Thus, it could be considered the most promising candidate for inhibiting various strains of EV-A71 3Cpro proteins in the newly anti-EV compounds group. Furthermore, the mutation at E71A has the most significant impact on the docking results of all ligands evaluated. Future in vitro experiments on Hesperidin’s ability to inhibit 3Cpro activity should be conducted to compare with FIOMC’s in vitro results and validate the current in silico work.