Yong-Jun Jiang

Ab initio calculations on halogen-bonded complexes and comparison with density functional methods

A systematic theoretical investigation on a series of dimeric complexes formed between some halocarbon molecules and electron donors has been carried out by employing both ab initio and density functional methods. Full geometry optimizations are performed at the Moller–Plesset second‐order perturbation (MP2) level of theory with the Dunnings correlation‐consistent basis set, aug‐cc‐pVDZ. Binding energies are extrapolated to the complete basis set (CBS) limit by means of two most commonly used extrapolation methods and the aug‐cc‐pVXZ (X = D, T, Q) basis sets series. The coupled cluster with single, double, and noniterative triple excitations [CCSD(T)] correction term, determined as a difference between CCSD(T) and MP2 binding energies, is estimated with the aug‐cc‐pVDZ basis set. In general, the inclusion of higher‐order electron correlation effects leads to a repulsive correction with respect to those predicted at the MP2 level. The calculations described herein have shown that the CCSD(T) CBS limits yield binding energies with a range of −0.89 to −4.38 kcal/mol for the halogen‐bonded complexes under study. The performance of several density functional theory (DFT) methods has been evaluated comparing the results with those obtained from MP2 and CCSD(T). It is shown that PBEKCIS, B97‐1, and MPWLYP functionals provide accuracies close to the computationally very expensive ab initio methods.

Molecular docking and molecular dynamics simulation studies of GPR40 receptor–agonist interactions

In order to explore the agonistic activity of small-molecule agonists to GPR40, AutoDock and GROMACS software were used for docking and molecular dynamics studies. A molecular docking of eight structurally diverse agonists (six carboxylic acids (CAs) agonist, and two non-carboxylic acids (non-CAs) agonist) was performed and the differences in their binding modes were investigated. Moreover, a good linear relationship based on the predicted binding affinities (pK(i)) determined by using AutoDock and experimental activity values (pEC50) was obtained. Then, the 10ns molecular dynamics (MD) simulations of three obtained ligand-receptor complexes embedded into the phospholipid bilayer were carried out. The position fluctuations of the ligands located inside the transmembrane domain were explored, and the stable binding modes of the three studied agonists were determined. Furthermore, the residue-based decomposition of interaction energies in three systems identified several critical residues for ligand binding.

3D-QSAR studies of HDACs inhibitors using pharmacophore-based alignment.

Histone deacetylases (HDACs) enzyme is a promising target for the development of anticancer drugs. The enzyme-bound conformation of Trichostatin A (TSA) (PDB ID:1C3R) as an inhibitor of HDACs was used to manually construct a pharmacophore model. This model was then successfully used to identify the bioactive conformation and align flexible and structurally diverse molecules. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on hydroxamate-based HDACs inhibitors based on phamacophore alignment. The best predictions were obtained with CoMFA standard model (q(2) = 0.726, r(2) = 0.998) and CoMSIA model combined with steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields (q(2) = 0.610, r(2) = 0.995). Both of the models were validated by an external test set, which gave a satisfactory predictive r(2) value of 0.800 and 0.732, respectively. Graphical interpretation of the results revealed important structural features of the inhibitors related to the active site of HDACs. The results may be exploited for further design and virtual screening for some novel HDACs inhibitors.

Role of bridging water molecules in GSK3β-inhibitor complexes: Insights from QM/MM, MD, and molecular docking studies

The role of water molecules is increasingly gaining interest in drug design, and several studies have highlighted their paramount contributions to the specificity and the affinity of ligand binding. In this study, we employ the two‐layer ONIOM‐based quantum mechanics/molecular mechanics (QM/MM) calculations, molecular dynamics (MD) simulations, and molecular docking studies to investigate the effect of bridging water molecules at the GSK3β‐inhibitors interfaces. The results obtained from the ONIOM geometry optimization and AIM analysis corroborated the presence of bridging water molecules that form hydrogen bonds with protein side chain of Thr138 and/or backbone of Gln185, and mediate interactions with inhibitors in the 10 selected GSK3β‐inhibitor complexes. Subsequently, MD simulations carried out on a representative system of 1R0E demonstrated that the bridging water molecule is stable at the GSK3β‐inhibitor interface and appears to contribute to the stability of the protein–inhibitor interactions. Furthermore, molecular docking studies of GSK3β‐inhibitor complexes indicated that the inhibitors can increase binding affinities and the better docked conformation of inhibitors can be obtained by inclusion of the bridging water molecules, especially for the flexible inhibitors, in docking experiments into individual protein conformations. Our results elucidate the importance of bridging water molecules at the GSK3β‐inhibitor interfaces and suggest that they might prove useful in rational drug design.

Molecular Modeling and Molecular Dynamics Simulation Studies of the GSK3β/ATP/Substrate Complex: Understanding the Unique P+4 Primed Phosphorylation Specificity for GSK3β Substrates

Substrate specificity of protein kinases is of fundamental importance for the integrity and fidelity of signaling pathways. Glycogen synthase kinase 3β (GSK3β) has a unique substrate specificity that prefers phosphorylation of its substrates at the P+4 serine before it can further phosphorylate the substrate at the P0 serine in the canonical motif SXXXS(p), where S(p) is the primed phosphorylation site. The detailed phosphorylation mechanism, however, is not clearly understood. In this study, a three-dimensional (3D) model of the ternary complex of GSK3β, ATP, and the phosphorylated glycogen synthase (pGS), termed GSK3β/ATP/pGS, is constructed using a hierarchical approach and by integrating molecular modeling and molecular dynamics (MD) simulations. Based on the 3D model, the substrate primed phosphorylation mechanism is investigated via two 12 ns comparative MD simulations of the GSK3β/ATP/pGS and GSK3β/ATP/GS systems, which differ in the phosphate group bound to the P+4 serine of GS. In agreement with structural analysis, computed binding free energies reveal that the binding of pGS to GSK3β is favored in the prephosphorylated state compared with the GS native state. More importantly, comparison with the system simulated without primed phosphorylation in the GSK3β/ATP/GS complex shows that for an optimal phosphorylation reaction to occur, the pGS priming phosphate in the GSK3β/ATP/pGS system optimizes the proper orientation of the GSK3β N- and C-terminal domains and clamps the P0 serine of pGS in the appropriate configuration for interaction with the ATP γ-phosphate within the catalytic groove.

Virtual screening for Raf-1 kinase inhibitors based on pharmacophore model of substituted ureas

A three-dimensional (3D) quantitative pharmacophore model was developed from a training set of structurally diverse substituted ureas against Raf-1 kinase, which was well validated to be highly predictive by two methods, namely, test set prediction and Cat-Scramble method. Then a virtual database searching was performed with the pharmacophore model as a 3D query, and the bioactivities of the retrieved hits were predicted by the pharmacophore. Subsequently, molecular docking was carried out on the selected hits whose estimated IC(50) was less than 1 microM. Finally, 29 hits were identified as potential leads against Raf-1 kinase, which exhibited good estimated activities, high docking scores, similar binding mode to experimentally proven compounds and favorable drug-like properties. The study may facilitate the discovery and rational design of novel leads with potent inhibitory activity targeting Raf-1 kinase.

Insights into unbinding mechanisms upon two mutations investigated by molecular dynamics study of GSK3β–axin complex: Role of packing hydrophobic residues

Glycogen synthase kinase 3β (GSK 3β) is a key component of several cellular processes including Wnt and insulin signalling pathways. The interaction of GSK3β with scaffolding peptide axin is thought to be responsible for the effective phosphorylation of β‐catenin, the core effector of Wnt signaling, which has been linked with the occurrence of colon cancer and melanoma. It has been demonstrated that the binding of axin to GSK3β is abolished by the single‐point mutation of Val267 to Gly (V267G) in GSK3β or Leu392 to Pro (L392P) in axin. Molecular dynamics (MD) simulations were performed on wild type (WT), V267G mutant and L392P one to elucidate the two unbinding mechanisms that occur through different pathways. Besides, rough energy and residue‐based energy decomposition were calculated by MM_GBSA (molecular mechanical Generalized_Born surface area) approach to illuminate the instability of the two mutants. The MD simulations of the two mutants and WT reveal that the structure of GSK3β remains unchanged, while axin moves away from the interfacial hydrophobic pockets in both two mutants. Axin exhibits positional shift in V267G mutant, whereas, losing the hydrogen bonds that are indispensable for stabilizing the helix structure of wild type axin, the helix of axin is distorted in L392P mutant. To conclude, both two mutants destroy the hydrophobic interaction that is essential to the stability of GSK3β‐axin complex. Proteins 2007.

Quantitative structure-chromatographic retention relationship for polycyclic aromatic sulfur heterocycles.

Polycyclic aromatic sulfur heterocycles (PASHs) are of concern in petroleum geochemistry and environmental chemistry. In the present study, geometrical optimization and electrostatic potential calculations have been performed for 114 PASHs reported previously at the HF/6-31G* level of theory. A group of 25 statistically based parameters have been extracted. Linear relationships between gas-chromatographic retention index (RI) and the structural descriptors have been established by stepwise linear regression analysis. The result shows that two quantities derived from positive electrostatic potential on molecular surface, V(s)(+) (the average value of the positive electrostatic potentials on molecular surface) and sigma(+)(2) (a measure of dispersion tendency of positive electrostatic potential), together with V(mc) (the molecular volume) and E(HOMO) (the energy of the highest occupied molecular orbital) can be well used to express the quantitative structure-retention relationship (QSRR) of PASHs. Predictive capability of the model has been demonstrated by leave-one-out cross-validation with the cross-validated correlation coefficient (R(CV)) of 0.992. Furthermore, when splitting the 114 PASH samples into calibration and test sets in the ratio of 2:1, a similar treatment yields an equation of almost equal statistical quality and very similar regression coefficients, validating the robustness of our model. Predictions for six PASHs from other source have also been made. The QSRR model established may provide a new powerful method for predicting chromatographic properties of aromatic organosulfur compounds.

Effect of mutation K85R on GSK-3β : Molecular dynamics simulation

As a serine-threonine protein kinase, glycogen synthase kinase-3 (GSK-3) regulates the synthesis of glycogen and plays important roles in several signaling pathways. It is a key therapeutic target for a number of diseases, such as diabetes, cancer, Alzheimers disease and chronic inflammation. The conserved Lys85 is important to GSK-3beta activity and in this paper we illustrate the significant role of Lys85 using dynamic simulation. We find that when Lys85 is mutated to Arg, one of the two conserved hydrogen bonds between Lys85 and ATP disappears, the salt bridge between Lys85 and Glu97 cannot form, and conformational changes of Phe93, Arg96 and Glu211 occur. These will cause conformational changes of the substrate binding groove that would inhibit the activity of GSK-3beta. MM-GBSA calculations reveal that the K85R mutation could lead to a less energy-favorable complex, which is consistent with the structural analysis.

Discovery of potential new InhA direct inhibitors based on pharmacophoreand 3D-QSAR analysis followed by in silico screening

This study develops an efficient approach for discovering new InhA direct inhibitors in theory. The InhA-bound conformation of a pyrrolidine carboxamide inhibitor was used to build a pharmacophore model. This model with feature-shape query was successfully used to identify and align the bioactive conformations of pyrrolidine carboxamide analogues and screen SPECS database. A statistically valid 3D-QSAR with good results (r(2)(cv)=0.660 and r(2)=0.962) was obtained. From database screening, 30 hits were selected and identified as potential leads, which exhibit good estimated activities by 3D-QSAR model. Docking studies were carried out on two representative hits to analyze their interactions with InhA. Also, the interactions between existing pyrazole inhibitors and InhA were explored based on the pharmacophore model.