Lung cancer is the most frequent cause of cancer-related deaths worldwide, and mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are a common cause of non-small-cell lung cancers, which is a major subtype of lung cancers. Recently, a series of 5-methylpyrimidine-pyridinone derivatives have been designed and synthesized as novel selective inhibitors of EGFR and EGFR mutants. However, the binding-based inhibition mechanism has not yet been determined. In this study, we carried out molecular dynamic simulations and free-energy calculations for EGFR derivatives to fill this gap. Based on the investigation, the three factors that influence the inhibitory effect of inhibitors are as follows: (1) The substitution site of the Cl atom is the main factor influencing the activity through steric effect; (2) The secondary factors are repulsion between the F atom (present in the inhibitor) and Glu762, and the blocking effect of Lys745 on the phenyl ring of the inhibitor. (3) The two factors function synergistically to influence the inhibitory capacity of the inhibitor. The theoretical results of this study can provide further insights that will aid the design of oncogenic EGFR inhibitors with high selectivity.

Streptococcus pneumoniae can cause diseases such as pneumonia. Broad-spectrum antibiotic therapy for Streptococcus pneumoniae is increasingly limited due to the emergence of drug-resistant strains. The development of novel drugs is still currently of focus. Abundant polyphenols have been demonstrated to have antivirus and antibacterial ability. Chlorogenic acid is one of the representatives that has been proven to have the potential to inhibit both the influenza virus and Streptococcus pneumoniae. However, for such a potential neuraminidase inhibitor, the interaction mechanism studies between chlorogenic acid and Streptococcus pneumoniae neuraminidase are rare. In the current study, the binding mechanism of chlorogenic acid and Streptococcus pneumoniae neuraminidase were investigated by molecular simulation. The results indicated that chlorogenic acid might establish the interaction with Streptococcus pneumoniae neuraminidase via hydrogen bonds, salt bridge, and cation-π. The vital residues involved Arg347, Ile348, Lys440, Asp372, Asp417, and Glu768. The side chain of Arg347 might form a cap-like structure to lock the chlorogenic acid to the active site. The results from binding energy calculation indicated that chlorogenic acid had strong binding potential with neuraminidase. The results predicted a detailed binding mechanism of a potential Streptococcus pneumoniae neuraminidase inhibitor, which will be provide a theoretical basis for the mechanism of new inhibitors.

Alzheimer’s disease (AD) is a specific neurodegenerative disease. This study adopts single-chain variable fragments (scFvs) as a potential immunotherapeutic precursor for AD. According to the remarkable effects of monoclonal antibodies, such as the depolymerization or promotion of Aβ42 efflux by Crenezumab, Solanezumab, and 12B4, it is attractive to prepare corresponding scFvs targeting amyloid-β-42 protein (Aβ42) and investigate their biological activities. Crenezumab-like scFv (scFv-C), Solanezumab-like scFv (scFv-S), and 12B4-like scFv (scFv-12B4) were designed and constructed. The thermal stabilities and binding ability to Aβ42 of scFv-C, scFv-S, and scFv-12B4 were evaluated using unfolding profile and enzyme-linked immunosorbent assay. As the results indicated that scFv-C could recognize Aβ42 monomer/oligomer and promote the disaggregation of Aβ42 fiber as determined by the Thioflavin-T assay, the potential mechanism of its interaction with Aβ42 was investigated using molecular dynamics analysis. Interactions involving hydrogen bonds and salt bonds were predicted between scFv-C and Aβ42 pentamer, suggesting the possibility of inhibiting further aggregation of Aβ42. The successfully prepared scFvs, especially scFv-C, with favorable biological activity targeting Aβ42, might be developed for a potentially efficacious clinical application for AD.

Diabetes mellitus, a chronic metabolic disorder, represents a serious threat to human health. The gut enzyme maltase–glucoamylase (MGAM) has attracted considerable attention as a potential therapeutic target for the treatment of type 2 diabetes. Thus, developing novel inhibitors of MGAM holds the promise of improving clinical management. The dipeptides, Thr-Trp (TW) and Trp-Ala (WA), are known inhibitors of MGAM; however, studies on how they interact with MGAM are lacking. The work presented here explored these interactions by utilizing molecular docking and molecular dynamics simulations. Results indicate that the active center of the MGAM could easily accommodate the flexible peptides. Interactions involving hydrogen bonds, cation-π, and hydrophobic interactions are predicted between TW/WA and residues including Tyr1251, Trp1355, Asp1420, Met1421, Glu1423, and Arg1510 within MGAM. The electrostatic energy was recognized as playing a dominant role in both TW-MGAM and WA-MGAM systems. The binding locations of TW/WA are close to the possible acid-base catalytic residue Asp1526 and might be the reason for MGAM inhibition. These findings provide a theoretical structural model for the development of future inhibitors.

E. coli thioesterase ‘TesA is an important enzyme in fatty acid production. Medium-chain fatty acids (MCFAs, C6-C10) are of great interest due to their similar physicochemical properties to petroleum-based oleo-chemicals. It has been shown that wild-type ‘TesA had better selectivity for long-chain acyl substrates (≥C16), while the two mutants ‘TesA^E142D/Y145G and ‘TesA^{M141L/E142D/Y145G} had better selectivity for medium-chain acyl substrates. However, it is difficult to obtain the selectivity mechanism of substrates for proteins by traditional experimental methods. In this study, in order to obtain more MCFAs, we analyzed the binding mode of proteins (‘TesA, ‘TesA^E142D/Y145G and ‘TesA^{M141L/E142D/Y145G}) and substrates (C16/C8-N-acetylcysteamine analogs, C16/C8-SNAC), the key residues and catalytic mechanisms through molecular docking, molecular dynamics simulations and the molecular mechanics Poisson–Boltzmann surface area (MM/PBSA). The results showed that several main residues related to catalysis, including Ser10, Asn73 and His157, had a strong hydrogen bond interaction with the substrates. The mutant region (Met141-Tyr146) and loop_107–113 were mainly dominated by Van der Waals contributions to the substrates. For C16-SNAC, except for ‘TesA^{M141L/E142D/Y145G} with large conformational changes, there were strong interactions at both head and tail ends that distorted the substrate into a more favorable high-energy conformation for the catalytic reaction. For C8-SNAC, the head and tail found it difficult to bind to the enzyme at the same time due to insufficient chain length, which made the substrate binding sites more variable, so ‘TesA^{M141L/E142D/Y145G} with better binding sites had the strongest activity, and ‘TesA had the weakest activity, conversely. In short, the matching substrate chain and binding pocket length are the key factors affecting selectivity. This will be helpful for the further improvement of thioesterases.