Quantitative Structure Activity Relationship Studies of Benzoxazinone Derivative Antithrombotic Drug Using New Three-dimensional Structure Descriptors

A novel three-dimensional holographic vector of atomic interaction field（3D-HoVAIF） was used to describe the chemical structures of 23 benzoxazinone derivatives as antithrombotic drugs.Here a quantitative structure activity relationship（QSAR） model was built by partial least-squares（PLS） regression.The estimation stability and prediction ability of the model were strictly analyzed by both internal and external validations.The correlation coefficients of established PLS model,leave-one-out（LOO） cross-validation,and predicted values versus experimental ones of external samples were R2=0.899,RCV2=0.854 and Qext2=0.868,respectively.These values indicated that the built PLS model had both favorable estimation stability and good prediction capabilities.Furthermore,the satisfactory results showed that 3D-HoVAIF could preferably express the information related to the biological activity of benzoxazinone derivatives.

Prediction of Stability for Polychlorinated Biphenyls in Transformer Insulation Oil Through Three-dimensional Quantitative Structure-activity Relationship Pharmacophore Model and Full Factor Experimental Design

Based on the obtained data of half-lives（t1/2） for 31 polychlorinated biphenyl congeners（PCBs）, 3D quantitative structure-activity relationship（QSAR） pharmacophore was used to establish a 3D QSAR model to predict the t1/2 values of the remaining 178 PCBs, using the structural parameters as independent variables and lgt1/2 values as the dependent variable. Among this process, the whole data set（31 compounds） was divided into a training set（24 compounds） for model generation and a test set（7 compounds） for model validation. Then, the full factor experimental design was used to research the potential second-order interactional effect between different substituent positions, obtaining the final regulation scheme for PCB. At last, a 3D QSAR pharmacophore model was established to validate the reasonable regulation targeting typical PCB with respect to half-lives and thermostability. As a result, the cross-validation correlation coefficient（q2） obtained by the 3D QSAR model was 0.845（〉0.5） and the coefficient of determination（r2） obtained was 0.936（〉0.9）, indicating that the models were robust and predictive. CoMSIA analyses upon steric, electrostatic and hydrophobic fields were 0.7%, 85.9%, and 13.4%, respectively. The electrostatic field was determined to be a primary factor governing the tt/2. From CoMSIA contour maps, tl/2 increased when substi- tuents possessed electropositive groups at the 2＇-, 3-, Y-, 5- and 5＇- positions and electronegative groups at the 3-, 3＇-, 5-, 6- and 6＇- positions, which could increase the PCB stability in transformer insulation oil. Modification of two typical PCB congeners（PCB-77 and PCB-81） showed that the lgtl/2 for three selected modified compounds increased by 13%（average ratio） compared with that of each congener and the thermostability of them were higher, validating the reasonability of the regulatory scheme obtained from the 3D QSAR model. These results are expected to be beneficial in predicting tl/2 values of PCB homologues and derivatives and in providing a theoretical foundation for further elucidation of the stability of PCBs.

Pharmacophore and Docking-based 3D-QSAR Studies on HIV-1 Integrase Inhibitors

Integrase（IN） plays an essential role in the process of HIV-1 replication.IN inhibitors of diketo acid derivatives（DKAs） were analysed by the Comparative Molecular Field Analysis（CoMFA） and Comparative Molecular Similarity Induces Analysis（CoMSIA） methods.A set of 42 compounds were randomly selected as the training set（35） and test set（7）.Firstly,a good pharmacophore（goodness of hit=0.787） was obtained and used to align ligands.Then,predictive models were constructed with the CoMFA and CoMSIA methods based on the pharmacophore alignment.As a result,the CoMS1A method yielded the best model with an r2 of 0.955 and a q2 of 0.665,which can predict the activities of the tested DKAs very well（r2=0.559）.Finally,DKAs were docked into IN,and the predicit modes were superimposed on the contour maps obtained from the best CoMSIA model.The superimposed maps gave a visualized and meaningful insight into the inhibitory behaviors,providing significantly useful information for the rational drug design of anti-IN agents.

3D-QSAR Study on the Inhibitory Activity of Flavonoids on PIM-1 Kinase

20 Typical flavonoids were selected for study on the interaction between them and PIM-1 kinase with the comparative molecular field analysis method（CoMFA） as well as the comparative molecular similarity index analysis method（CoMSIA） based on molecule docking.3D-QSAR models between these flavonoids and receptor PIM-1 kinase were established.The obtained optimal cross-validation correlation coefficient Q2 for CoMFA model was 0.582,and the non-cross-validation correlation coefficient R2 was 0.955;the corresponding values for CoMSIA model were 0.790 and 0.974,respectively.These two models showed fairly fine stability and predictive ability.In addition,molecule docking results revealed the key residues in the receptor cavity and their specific action ways with flavonoids.

QSAR Studies on Influenza Neuraminidase Inhibitors——Acylthiourea Analogue

The quantitative structure-activity relationship （QSAR） of 30 acylthiourea analogues was studied by using a three-dimensional holographic vector of atomic interaction field （3D-HoVAIF） to describe their chemical structures. The descriptors obtained were screened by stepwise multiple regression （SMR） and a partial least-squares （PLS） regression model was built. The correlation coefficient r^2 of the established model and Leave-One-Out （LOO） Cross-Validation （CV） correlation coefficient q^2 are 0.624 and 0.409, respectively. The model has favorable stability and good prediction capability, and further QSAR analysis showed that hydrophobic interaction has the most important effect on the activity of acylthiourea analogue and 3D-HoVAIF was applicable to the molecular structural characterization and biologicalactivity prediction.

Topomer CoMFA, HQSAR Studies and Molecular Docking of 2,5-Diketopiperazine Derivatives as Oxytocin Inhibitors

Topomer comparative molecular field analysis(Topomer Co MFA)and holographic quantitative structure-activity relationship(HQSAR)for 1302,5-diketopiperazine derivatives were used to build a three-dimensional quantitative structure-activity relationship(3D-QSAR)model.The results show that the models have high predictive ability.For Topomer CoMFA,the cross-validated q^2 value is 0.710 and the non-cross-validated r^2 value is 0.834.The most effective HQSAR model shows that the cross-validation q^2 value is 0.700,the non-cross-validated r^2 value is 0.815,and the best hologram length value is 353 using connections and bonds as fragment distinctions.50 highly active 2,5-diketopiperazine derivatives were designed based on the three-dimensional equipotential map and HQSAR color code map.Finally,the molecular docking method was also used to study the interactions of these new molecules by docking the ligands into the diketopiperazine active site,which revealed the likely bioactive conformations.This study showed that there are extensive interactions between the new molecule and Arg156,Arg122 residues in the active site of diketopiperazine.These results provide useful insights for the design of potent of the new 2,5-diketopiperazine derivatives.

Study on the Biological Activity of 3-Aroyl-5-substituted Thiophene Derivatives Based on the CoMFA Method

A three-dimensional quantitative structure-activity relationship(3 D-QSAR) study was conducted to analyze the A1 AR density(Bmax) of 56 3-aroyl-5-substituted thiophene derivatives(ASTDs) in human A1 Chinese hamster ovary(hA1 CHO) membranes by the comparative molecular field analysis(CoMFA) method. A training set of 45 compounds was used to establish the predictive model, which was verified by the test set of 17 compounds containing template molecule and 5 newly designed molecules. The cross-validation(R2 cv) and non-cross-validation(R2) coefficients of the training set were 0.655 and 0.959, respectively. The model was used to predict the activities of the compounds of the training and test sets, and the results indicated that the models had strong stability and good prediction ability. According to model analysis, the contribution of steric and electrostatic fields was 51.4% and 48.6%, respectively. Based on the 3 D contour maps, five excellent ASTDs agonists were designed, which need to be further verified by biomedical experiments.

Key Parameters Analysis and Regulation of Singlet Oxygen Quenching Rate of Carotenoids

28 kinds of carotenoids are studied to reveal the key parameters and regulation on the singlet oxygen quenching rate.First,the quantum chemistry parameters of carotenoids calculated by Gaussian software combined with substitution parameters were used to construct the quantitative structure-activity relationship model(QSAR)of the singlet oxygen quenching rate of carotenoids.The key parameters affecting the antioxidant activity of carotenoids are revealed,and the data predicted via the QSAR model were provided for subsequent research.Then,a three-dimensional(3D)pharmacophore model was used to regulate and modify the antioxidant activity of carotenoids.The correlation coefficients of the modeling group(R2)and verification group(Rpre2)of the established QSAR model were 0.945 and 0.916,respectively,which can be used for the analysis of antioxidant activity of carotenoids;the antioxidant activity of carotenoids can be significantly regulated by the number of conjugated C=C bonds,the energy difference between frontier molecular orbitals and the partial Mulliken charge in C1 and theπ···π*excitation energy E(s);the antioxidant activity of carotenoids can be effectively regulated by the hydrogen bond acceptor pharmacophores on both sides of the conjugated C=C bonds and the hydrophobic groups on the conjugated C=C bond;the hydrophobic substituents attached to conjugated C=C bonds can effectively improve the singlet oxygen quenching rate of carotenoids.

Computational Investigations about the Effects of Heteromolecular Aggregation on Bioactivities:a Case of Neonicotinoids and Water

Molecular aggregation state of bioactive compounds plays a key role in bio-interactive procedure.Diverse ag-gregation states of bioactive compounds contribute to different biological or chemical properties.Water-bridge,as the simple hetero-molecular aggregation,has been found bridging the binding between many bioactive compounds and their targets through hydrogen bonding network,e.g.in the recognition of neonicotinoids with insect nAChRs.To better understanding the roles of water-bridge on bioactivities of compounds,an approach of hetero-dimeric ag-gregation with water was proposed.Quantitative structure-activity relationship(QSAR)and pharmacophore mod-eling investigations were applied on 19 neonicotinoids,as well as their aggregates with water.The aggregate-based CoMSIA,PHASE and linear QSAR models presented better statistical significance and predictabilities than the monomer ones,which indicated that the bioactivities correlated with the aggregate properties and water bridged hy-drogen bond of the active site.All results revealed the essential roles of water-bridge in ligand recognition,which should be considered in future ligand design and optimization.

3D-QSAR studies on glycogen phosphorylase inhibitors by flexible comparative molecular field analysis

Canceling grids accommodating probes in comparative molecular field analysis (CoMFA), the idea of flexibleness is introduced into the CoMFA, and in combination with swarm intelligent algorithm which attempts to optimize distributions of diverse probes around drug molecules, a new 3D-QSAR method is proposed in this context as flexible comparative molecular field analysis (FCoMFA). In preliminary at-tempts to performing QSAR studies on 47 glycogen phosphorylase inhibitors, FCoMFA is employed and confirmed to be potent to exploring ligand-receptor interaction manners at active positions and thus to generating stable and predictable models. Simultaneously by an intuitive graphics regarding probe distribution patterns, impacts of different substituted groups on activities is also given an insight into.

Insulation and Flame Retardancy Improvement of PBDEs Using 3D-QSAR Model Combined with a Fuzzy Membership Function Method

A three-dimensional quantitative structure-activity relationship(3D-QSAR)model based on the fuzzy membership function method was developed in this study,and then the model was applied to the molecular design of the enhanced comprehensive activities(insulation/flame retardancy)of polybrominated diphenyl ethers(PBDEs)considering their environmental behavior control,to develop environmental-friendly PBDE derivatives with outstanding functionality.Firstly,a fuzzy membership function method was employed to characterize the evaluation values of comprehensive activities of the functional properties of PBDEs based on the 3D-QSAR model.Secondly,a comprehensive activity 3D-QSAR model(CoMFA)of the functional properties of PBDEs was established,which demonstrated robustness and good predictive ability.Thirdly,a molecular modification scheme was designed to enhance the comprehensive activity of the functional properties of PBDEs considering the PBDE homologs BDE-138,BDE-183,and BDE-209 as target molecules.The resulting information indicated that the four PBDE derivatives with significantly enhanced functional properties,such as passing screening for toxicity,bioconcentration,migration,and biodegradability assessments with environmentally friendly results,were successfully designed(43.57%-82.14%enhancement).Finally,the mechanism analysis indicated that the enhanced functional properties of the modified PBDE derivatives were significantly related to the substitution positions and substitution groups of PBDEs.