Jiagao Cheng

Probing ligand binding modes of human cytochrome P450 2J2 by homology modeling, molecular dynamics simulation, and flexible molecular docking

Cytochrome P450 (P450) 2J2 catalyzes epoxidation of arachidonic acid to eicosatrienoic acids, which are related to a variety of diseases such as coronary artery disease, hypertension, and carcinogenesis. Recent experimental data also suggest that P450 2J2 could be a novel biomarker and a potential target for cancer therapy. However, the active site topology and substrate specificity of this enzyme remain unclear. In this study, a three‐dimensional model of human P450 2J2 was first constructed on the basis of the crystal structure of human P450 2C9 in complex with a substrate using homology modeling method, and refined by molecular dynamics simulation. Flexible docking approaches were then employed to dock four ligands into the active site of P450 2J2 in order to probe the ligand‐binding modes. By analyzing the results, active site architecture and certain key residues responsible for substrate specificity were identified on the enzyme, which might be very helpful for understanding the enzymes biological role and providing insights for designing novel inhibitors of P450 2J2. Proteins 2008.

Design, Synthesis, Crystal Structures, and Insecticidal Activities of Eight-Membered Azabridge Neonicotinoid Analogues

Three series of novel azabridge neonicotinoid analogues were designed and synthesized, which were constructed by starting material A, glutaraldehyde, and primary amine hydrochlorides (aliphatic amines, phenylhydrazines, and anilines). Most of the eight-membered azabridge compounds presented higher insecticidal activities than oxabridged compound B against cowpea aphid (Aphis craccivora) and brown planthopper (Nilaparvata lugens). Compared with imidacloprid, some azabridged compounds exhibited excellent insecticidal activity against brown planthopper. The crystal structures and bioassay indicated that changing bridge atoms from O to N could lead to entirely different conformations, which might be the important influential factor of the bioactivities.

Design, synthesis, crystal structure analysis, and insecticidal evaluation of phenylazoneonicotinoids.

On the basis of research of the proposed modes of action between neonicotinoids and insect nicotinic acetylcholine receptor (nAChR), a series of phenylazoneonicotinoids were designed and synthesized to further promote the π-π interaction between molecule and amino acid residues. The target compounds have been identified on the basis of satisfactory analytical and spectral ((1)H NMR, (13)C NMR, HRMS, and X-ray) data. The preliminary results revealed that tiny differences in substitutes resulted in different configurations and great bioactivity variations. Some compounds with electron-donating groups on positions 2 and 6 of the phenyl ring presented higher insecticidal activity than imidacloprid against cowpea aphids ( Aphis craccivora ). The impressive crystal structure of the excellent insecticidal activity compound 9q clearly proved that the functional electronegative pharmacophore was approximately vertical to the methyleneimidazolidine plane. The differences in the mode of interaction on nAChR of typical compounds 9h and 9q remain unclear.

Computational Insights into the Different Resistance Mechanism of Imidacloprid versus Dinotefuran in Bemisia tabaci

Insecticide resistance is a critical problem for pest control and management. For Bemisia tabaci, striking high metabolic resistance (generally conferred by CYP6CM1) was observed for imidacloprid (IMI) and most other neonicotinoid members. However, dinotefuran (DIN) displayed very low resistance factors, which indicated distinct metabolic properties. Here, molecular modeling methods were applied to explore the different resistance features of IMI versus DIN within the Q type of CYP6CM1. It was found that Arg225 played crucial roles in the binding of IMI-CYP6CM1vQ with a cation-π interaction and two stable H-bonds; however, such interactions were all absent in the DIN-CYP6CM1vQ system. The stable binding of IMI with CYP6CM1vQ would facilitate the following metabolic reaction, while the weak binding of DIN might disable its potential metabolism, which should be an important factor for their distinct resistance levels. The findings might facilitate future design of the antiresistance neonicotinoid molecules.

Seven-Membered Azabridged Neonicotinoids: Synthesis, Crystal Structure, Insecticidal Assay, and Molecular Docking Studies

To study the influence of the ring sizes, 37 novel seven-membered azabridged neonicotinoid analogues were synthesized by reactions of nitromethylene analogues, succinaldehyde, and aniline hydrochlorides. Most of the title compounds presented higher insecticidal activities than that of imidacloprid (IMI), cycloxaprid (CYC), and eight-membered compounds against cowpea aphid (Aphis craccivora), armyworm (Pseudaletia separata Walker), and brown planthopper (Nilaparvata lugens), which indicated that introducing the structure of a seven-membered azabridge could significantly improve the insecticidal activities of neonicotinoid analogues. Docking study and binding mode analysis also revealed that introducing methyl group into position 2 of phenyl ring could increase the hydrophobic interactions with receptor, which implied that position 2 might be the key site to get high insecticidal compounds.

Pharmacophore, 3D-QSAR, and Bayesian model analysis for ligands binding at the benzodiazepine site of GABAA receptors: the key roles of amino group and hydrophobic sites.

Ligands binding at the benzodiazepine site of GABAA receptor play important pharmacological roles in clinical application. In this study, ligand‐based pharmacophore modeling, 3D‐QSAR analysis, and Bayesian model studies have been performed on a set of 84 diverse ligands binding at the benzodiazepine site. The results showed the best pharmacophore hypothesis AADHR.4, which included two hydrogen acceptors (A), one hydrogen donor (D), one hydrophobic group (H), and one aromatic ring (R). Atom‐based 3D‐QSAR model was built, and it showed good statistical significance (R2 = 0.936) and excellent predictive ability (Q2 = 0.821). Moreover, Bayesian model was developed and used to identify the key molecular features which are good or bad for the ligand binding activity. All the results from the pharmacophore, 3D‐QSAR, and Bayesian modeling studies revealed that a hydrogen‐bond donor (e.g., N‐H) and a hydrophobic group (e.g., Br) are critical structural features for the ligands binding at the benzodiazepine site.

Novel dimer based descriptors with solvational computation for QSAR study of oxadiazoylbenzoyl‐ureas as novel insect‐growth regulators

Molecular aggregation state of bioactive compounds plays a key role in its bio‐interactive procedure. In this article, based on the structure information of dimers, the simplest model of molecular aggregation state, and combined with solvational computation, total four descriptors (ΔV, MR2, ΔE1, and ΔE2) were calculated for QSAR study of a novel insect‐growth regulator, N‐(5‐phenyl‐1,3,4‐oxadiazol‐2‐yl)‐N′‐benzoyl urea. Two QSAR models were constructed with r2 = 0.671, q2 = 0.516 and r2 = 0.816, q2 = 0.695, respectively. It implicates that the bioactivity may strongly depend on the characters of molecular aggregation state, especially on the dimeric transport ability from oil phase to water phase.

Azobenzene Modified Imidacloprid Derivatives as Photoswitchable Insecticides: Steering Molecular Activity in a Controllable Manner

Incorporating the photoisomerizable azobenzene into imidacloprid produced a photoswitchable insecticidal molecule as the first neonicotinoid example of remote control insecticide performance with spatiotemporal resolution. The designed photoswitchable insecticides showed distinguishable activity against Musca both in vivo and in vitro upon irradiation. Molecular docking study further suggested the binding difference of the two photoisomers. The generation of these photomediated insecticides provides novel insight into the insecticidal activity facilitating further investigation on the functions of insect nicotinic acetylcholine receptors and opens a novel way to control and study insect behavior on insecticide poisoning using light.

Synthesis and Biological Evaluation of Nitromethylene Neonicotinoids Based on the Enhanced Conjugation

The neonicotinoids with a nitroconjugated system had excellent bioactivity, which could rival imidacloprid, and has been previously reported. However, the photodegradation and hydrolysis of this series of neonicotinoids was very quick according to our further investigation, which cannot be developed as a pesticide further. The approach to further enhance the conjugation was tried not only to increase the bioactivities but also to improve the stability in water and in the sun. A substituted phenyl group was introduced into the furan ring of compound 3. A total of 13 novel neonicotinoid analogues with a higher conjugation system were designed and synthesized. The target molecular structures have been confirmed on the basis of satisfactory analytical and spectral data. All compounds presented significant insecticidal activities on cowpea aphid ( Aphis craccivora ), cotton aphid ( Aphis gossypii ), and brown planthopper ( Nilaparvata lugens ). The stability test exhibited that the stability of novel analogues in water and under the mercury lamp has been improved significantly in comparison to compound 3.

QSAR and molecular docking studies on oxindole derivatives as VEGFR-2 tyrosine kinase inhibitors.

Abstract The three-dimensional quantitative structure–activity relationships (3D-QSAR) were established for 30 oxindole derivatives as vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitors by using comparative molecular field analysis (CoMFA) and comparative similarity indices analysis comparative molecular similarity indices analysis (CoMSIA) techniques. With the CoMFA model, the cross-validated value (q2) was 0.777, the non-cross-validated value (R2) was 0.987, and the external cross-validated value () was 0.72. And with the CoMSIA model, the corresponding q2, R2 and values were 0.710, 0.988 and 0.78, respectively. Docking studies were employed to bind the inhibitors into the active site to determine the probable binding conformation. The binding mode obtained by molecular docking was in good agreement with the 3D-QSAR results. Based on the QSAR models and the docking binding mode, a set of new VEGFR-2 tyrosine kinase inhibitors were designed, which showed excellent predicting inhibiting potencies. The result revealed that both QSAR models have good predictive capability to guide the design and structural modification of homologic compounds. It is also helpful for further research and development of new VEGFR-2 tyrosine kinase inhibitors.