Jian-Wei Zou

3D-QSAR studies on 4-Hydroxyphenylpyruvate Dioxygenase inhibitors by comparative molecular field analysis (CoMFA)

A comparative molecular field analysis (CoMFA) of alkanoic acid 3-oxo-cyclohex-1-enyl ester and 2-acylcyclohexane-1,3-dione derivatives of 4-hydroxyphenylpyruvate dioxygenase inhibitors has been performed to determine the factors required for the activity of these compounds. The substrates conformation abstracted from dynamic modeling of the enzyme-substrate complex was used to build the initial structures of the inhibitors. Satisfactory results were obtained after an all-space searching procedure, performing a leave-one out (LOO) cross-validation study with cross-validation q(2) and conventional r(2) values of 0.779 and 0.989, respectively. The results provide the tools for predicting the affinity of related compounds, and for guiding the design and synthesis of new HPPD ligands with predetermined affinities.

Theoretical studies on tautomerism of benzoylcyclohexane-1,3-dione and its derivatives

Abstract In the present paper, geometry optimizations were performed at HF/6-31G ∗ level for all of the possible tautomers of benzoylcyclohexanedione. For one triketone and two cis -endocyclic double bond enol tautomers that have lowest energies, extensive calculations were performed. The effect of calculation method and the size of the basis set on the relative stability of the tautomers were investigated. In addition, the tautomeric equilibrium constants and the energy barrier of the benzoylcyclohexane-1,3-diones were calculated. The solvent effect was fully considered when calculating the equilibrium constants and the results were analyzed by comparing with the experimental results. Finally, calculations were performed on representative 2-substituted benzoylcyclohexane-1,3-dione derivatives. It appears that the free energy of tautomerization and their HPPD inhibitive activity correlated closely.

The effect of Li+ on GSK-3 inhibition: Molecular dynamics simulation

Glycogen synthase kinase-3 (GSK-3) is a kind of serine-threonine protein kinase. It places important roles in several signaling pathways and it is a key therapeutic target for a number of diseases, such as diabetes, cancer, Alzheimer’s disease and chronic inflammation. Mg2+ ions which interact with ATP are conserved in GSK. They are important in phosphoryl transfer. Li+ is an inhibitor for GSK-3. It is used to treat bipolar mood disorder. This paper illustrates the effect of Li+ on GSK-3. When MgI2+ is replaced by Li+, the atom fluctuation of GSK-3 will rise, and the in-line phosphoryl transfer mechanism is probably demolished and the binding of pre-phosphorylated substrates may be disturbed. All the results we obtained clearly suggest that inhibition to GSK-3 is caused by the MgI2+ replacement with Li+.

Toward a uniform description of hydrogen bonds and halogen bonds: correlations of interaction energies with various geometric, electronic and topological parameters

Halogen bonds, which are specific non-covalent interactions similar to hydrogen bonds, play crucial roles in fields as diverse as supramolecular assemblies, crystal engineering, and biological systems. A total of 108 halogen-bonded and hydrogen-bonded complexes formed by different electron acceptors and NH3, namely, R–A⋯NH3 (A = H, Cl, Br or I), have been investigated at the MP2(full)/aug-cc-pVDZ(-PP) level of theory. The relationships between the interaction strengths and various geometric and electronic structures, as well as topological properties, were established, with a particular focus on the uniformity of these two types of interaction. The dependence of the BSSE-corrected interaction energy (ΔEcor) on the interatomic distance (rA⋯N) appeared to be nonlinear for both halogen-bonded and hydrogen-bonded systems; the relationship between ΔEcor and the difference between rA⋯N and the sum of the van der Waals radii (ΔrA⋯N) can be fitted to a combined quadratic regression equation. Furthermore, we demonstrated that the linear correlations between ΔEcor and ρb(BCP) (the electron density at bond critical points in the A⋯N bond) and its Laplacian ∇2ρb(BCP) can be used to provide a combined description of hydrogen bonds and halogen bonds, with correlation coefficients of 0.964 and 0.956, respectively. The dependence of the interaction strength on the electrostatic potential corresponding to an electron density of 0.002 a.u. along the R–A bond vector (ESP0.002), the amount of charge transferred (QCT) and the second-order perturbation stabilization energies of n(NH3) → σ*(R–A) (E(2)) were also examined. Strong halogen-bonded complexes were found to exhibit different linear correlations from weak halogen-bonded and hydrogen-bonded systems. Nevertheless, for the latter two types of system, a uniform regression equation can be constructed. These relationships not only improve our understanding of the nature of halogen bonding but also provide a feasible approach for predicting or determining the relative strengths of hydrogen bonds and halogen bonds, in particular when both types of non-covalent interaction coexist and compete with each other.

Role of Arg228 in the phosphorylation of galactokinase: the mechanism of GHMP kinases by quantum mechanics/molecular mechanics studies.

GHMP kinases are a group of structurally related small molecule kinases. They have been found in all kingdoms of life and are mostly responsible for catalyzing the ATP-dependent phosphorylation of intermediary metabolites. Although the GHMP kinases are of clinical, pharmaceutical, and biotechnological importance, the mechanism of GHMP kinases is controversial. A catalytic base mechanism was suggested for mevalonate kinase that has a structural feature of the γ-phosphate of ATP close to an aspartate residue; however, for one GHMP family member, homoserine kinase, where the residue acting as general base is absent, a direct phosphorylation mechanism was suggested. Furthermore, it was proposed by some authors that all the GHMP kinases function by a similar mechanism. This controversy in mechanism has limited our ability to exploit these enzymes as drug targets and in biotechnology. Here the phosphorylation reaction mechanism of the human galactokinase, a member of the GHMP kinase family, was investigated using molecular dynamics simulations and density functional theory-based quantum mechanics/molecular mechanics calculations (B3LYP-D/AMBER99). The reaction coordinates were localized by potential energy scan using an adiabatic mapping method. Our results indicate that a highly conserved Glu174 captures Arg105 in the proximity of the α-phosphate of ATP, forming a H-bond network; therefore, the mobility of ATP in the large oxyanion hole is restricted. Arg228 functions to stabilize the negative charge developed at the β,γ-bridging oxygen of the ATP during bond cleavage. The reaction occurs via a direct phosphorylation mechanism, and the Asp186 in the proximity of ATP does not directly participate in the reaction pathway. Because Arg228 is not conserved among GHMP kinases, reagents which form interactions with Arg228, and therefore can interrupt its function in phosphorylation, may be developed into potential selective inhibitors for galactokinase.

Correlation between empirical solvent polarity scales and computed quantities derived from molecular surface electrostatic potentials

Analysis of five empirical solvent polarity scales ETN, π*, Py, S′ and SPP is carried out by correlating them with Π and σ2tot, two computed quantities derived from molecular surface electrostatic potentials. Our results indicate (i) that the S′ scale should be a good global solvent polarity scale, (ii) that it would be inappropriate to use the ETN and Py scales to describe non-specific solute–solvent interactions for protic solvents, and (iii) that the π* and SPP scales are probably contaminated with charge-transfer effects for aromatic and polychlorinated solvents. The differences between our results and those obtained by the correlation of empirical scales with a theoretical thermodynamic analysis result (EPNA) are discussed in the context of intermolecular interactions between the probe nsolutes and the solvent considered.

Phosphorylation Mechanism of Phosphomevalonate Kinase: Implications for Rational Engineering of Isoprenoid Biosynthetic Pathway Enzymes

The mevalonate pathway is of important clinical, pharmaceutical, and biotechnological relevance. However, lack of the understanding of the phosphorylation mechanism of the kinases in this pathway has limited rationally engineering the kinases in industry. Here the phosphorylation reaction mechanism of a representative kinase in the mevalonate pathway, phosphomevalonate kinase, was studied by using molecular dynamics and hybrid QM/MM methods. We find that a conserved residue (Ser106) is reorientated to anchor ATP via a stable H-bond interaction. In addition, Ser213 located on the α-helix at the catalytic site is repositioned to further approach the substrate, facilitating the proton transfer during the phosphorylation. Furthermore, we elucidate that Lys101 functions to neutralize the negative charge developed at the β-, γ-bridging oxygen atom of ATP during phosphoryl transfer. We demonstrate that the dissociative catalytic reaction occurs via a direct phosphorylation pathway. This is the first study on the phosphorylation mechanism of a mevalonate pathway kinase. The elucidation of the catalytic mechanism not only sheds light on the common catalytic mechanism of the GHMP kinase superfamily but also provides the structural basis for engineering the mevalonate pathway kinases to further exploit their applications in the production of a wide range of fine chemicals such as biofuels or pharmaceuticals.

Quantitative structure-hydrophobicity relationships of molecular fragments and beyond.

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 Rekkers 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.

Interactions between pyrazole derived enantiomers and Chiralcel OJ: Prediction of enantiomer absolute configurations and elution order by molecular dynamics simulations

The separation of enantiomers and confirmation of their absolute configurations is significant in the development of chiral drugs. The interactions between the enantiomers of chiral pyrazole derivative and polysaccharide-based chiral stationary phase cellulose tris(4-methylbenzoate) (Chiralcel OJ) in seven solvents and under different temperature were studied using molecular dynamics simulations. The results show that solvent effect has remarkable influence on the interactions. Structure analysis discloses that the different interactions between two isomers and chiral stationary phase are dependent on the nature of solvents, which may invert the elution order. The computational method in the present study can be used to predict the elution order and the absolute configurations of enantiomers in HPLC separations and therefore would be valuable in development of chiral drugs.

Identification of Peptide Inhibitors of Enveloped Viruses Using Support Vector Machine

The peptides derived from envelope proteins have been shown to inhibit the protein-protein interactions in the virus membrane fusion process and thus have a great potential to be developed into effective antiviral therapies. There are three types of envelope proteins each exhibiting distinct structure folds. Although the exact fusion mechanism remains elusive, it was suggested that the three classes of viral fusion proteins share a similar mechanism of membrane fusion. The common mechanism of action makes it possible to correlate the properties of self-derived peptide inhibitors with their activities. Here we developed a support vector machine model using sequence-based statistical scores of self-derived peptide inhibitors as input features to correlate with their activities. The model displayed 92% prediction accuracy with the Matthew’s correlation coefficient of 0.84, obviously superior to those using physicochemical properties and amino acid decomposition as input. The predictive support vector machine model for self- derived peptides of envelope proteins would be useful in development of antiviral peptide inhibitors targeting the virus fusion process.