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Effective novel peptide inhibitors which targeted the domain III of the dengue envelope (E) protein by blocking dengue virus (DENV) entry into target cells, were identified. The binding affinities of these peptides towards E-protein were evaluated by using a combination of docking and explicit solvent molecular dynamics (MD) simulation methods. The interactions of these complexes were further investigated by using the Molecular Mechanics-Poisson Boltzmann Surface Area (MMPBSA) and Molecular Mechanics Generalized Born Surface Area (MMGBSA) methods. Free energy calculations of the peptides interacting with the E-protein demonstrated that van der Waals (vdW) and electrostatic interactions were the main driving forces stabilizing the complexes. Interestingly, calculated binding free energies showed good agreement with the experimental dissociation constant (Kd) values. Our results also demonstrated that specific residues might play a crucial role in the effective binding interactions. Thus, this study has demonstrated that a combination of docking and molecular dynamics simulations can accelerate the identification process of peptides as potential inhibitors of dengue virus entry into host cells.

Quantitative structure-property relationship (QSPR) models were firstly established for the hydrophobic substituent constant (πX) using the theoretical descriptors derived solely from electrostatic potentials (EPSs) at the substituent atoms. The descriptors introduced are found to be related to hydrogen-bond basicity, hydrogen-bond acidity, cavity, or dipolarity/polarizability terms in linear solvation energy relationship, which endows the models good interpretability. The predictive capabilities of the models constructed were also verified by rigorous Monte Carlo cross-validation. Then, eight groups of meta- or para-disubstituted benzenes and one group of substituted pyridines were investigated. QSPR models for individual systems were achieved with the ESP-derived descriptors. Additionally, two QSPR models were also established for Rekker's fragment constants (foct), which is a secondary-treatment quantity and reflects average contribution of the fragment to logP. It has been demonstrated that the descriptors derived from ESPs at the fragments, can be well used to quantitatively express the relationship between fragment structures and their hydrophobic properties, regardless of the attached parent structure or the valence state. Finally, the relations of Hammett σ constant and ESP quantities were explored. It implies that σ and π, which are essential in classic QSAR and represent different type of contributions to biological activities, are also complementary in interaction site.

Chiral hydantoins display potential antidepressant and anticancer activities. The quantitative structure property relationship (QSPR) study on chiral compounds plays a key role in predicting the retention factor and the separation factor even the elution order of the enantiomers. In this study, the structures of chiral arylhydantoin compounds have been built to compute molecular structural parameters using VolSurf program. The satisfying models were established between the parameters and the retention factor as well as the separation factor. Analysis on the variables shows that the large difference values of volume, hydrophilic regions and hydrogen bond acceptor and donor regions at some energy levels will result in the large separation factor. The differences of hydrophobic regions and the unbalance between the centre of mass and the barycentre of the hydrophobic region at high energy levels are also favorable to the separation. The differences of surface area, hydrophilic regions and hydrogen bond acceptor and donor regions at other energy levels as well as hydrophobic regions and the unbalance at low energy levels between the enantiomers are disadvantageous to the separation. The analysis on the chiral recognition mechanism demonstrates that the differences of the interaction energies between the enantiomers are mainly affected by the hydrogen bond, π-π interaction and CH3-π interaction. The retention factor and the separation factor, especially the elution order of the enantiomers can be easily predicted using the models. The study provides a helpful guidance for studying other chiral compounds.

Graphical abstract Highlights ► Comparative molecular dynamics simulations on HIV-1 IN bound with L-731,988, L-708,906 and S-1360. ► The acidic end of all the DKA inhibitors studied formed favourable ionic interactions with Lys159. ► The keto–enol parts of these compounds were consistently coordinated to Mg. ► The catalytic residue Glu152 formed a favourable ion–pair interaction with the negatively charged Arg199 on α6 in the most potent DKA inhibitors. ► The complexation with Merck inhibitors and S-1360 significantly constrained the flexible surface loop into an extended or open conformation., HIV-1 integrase (IN) has become an attractive target since drug resistance against HIV-1 reverse transcriptase (RT) and protease (PR) has appeared. Diketo acid (DKA) inhibitors are potent and selective inhibitors of HIV-1 IN: however the action mechanism is not well understood. Here, to study the inhibition mechanism of DKAs we performed 10 ns comparative molecular dynamics simulations on HIV-1 IN bound with three most representative DKA inhibitors: Shionogi inhibitor, S-1360 and two Merck inhibitors L-731,988 and L-708,906. Our simulations show that the acidic part of S-1360 formed salt bridge and cation–π interactions with Lys159. In addition, the catalytic Glu152 in S-1360 was pushed away from the active site to form an ion–pair interaction with Arg199. The Merck inhibitors can maintain either one or both of these ion–pair interaction features. The difference in potencies of the DKA inhibitors is thus attributed to the different binding modes at the catalytic site. Such structural information at atomic level, not only demonstrates the action modes of DKA inhibitors but also provides a novel starting point for structural-based design of HIV-1 IN inhibitors.