Charge Neutralization Strategy to Construct Salt-Tolerant and Cell-Permeable Nanoprobes: Application in Ratiometric Sensing and Imaging of Intracellular pH.

Intracellular pH homeostasis is essential for the survival and function of biological cells. Negatively charged molecular probes, such as pyranine (HPTS), tend to exhibit poor salt tolerance and unsatisfactory cell permeability, limiting their widespread use in intracellular assays. Herein, we explored a charge neutralization strategy using multicharged cationic nanocarriers for an efficient and stable assembly with the pH-sensitive HPTS. Through immobilization and neutralization with poly(allylamine hydrochloride)-stabilized red-emitting gold nanoclusters (PAH-AuNCs), the resulting nanoprobes (HPTS-PAH-AuNCs) offered improved salt tolerance, satisfactory cell permeability, and dual-emission properties. The fluorescence ratio exhibited a linear response over the pH range of 3.0-9.0. Moreover, the proposed HPTS-PAH-AuNCs were successfully applied to determine and visualize lysosomal pH variations in living cells, which indicated great potential for biosensing and bioimaging applications in living systems. Benefiting from the charge neutralization strategy, various types of probes can be expected to achieve broader analytical applications.

Evaluation of the extension of rotation ambiguity associated to multivariate curve resolution solutions by the application of the MCR-BANDS method.

Multivariate Curve Resolution (MCR) methods have been widely used to resolve the spectra (instrumental responses) and concentration profiles of the unknown constituents of chemical mixtures especially when no prior information is available about the nature and composition of these mixtures. Based on the fulfillment of a bilinear model, like the multivariate extension of Beer's law, MCR solutions are affected by rotation ambiguity, which means that a range of feasible solutions can explain the observed data equally well fulfilling the same constraints. The MCR-BANDS method has been proposed to provide a measure of the extension of rotation ambiguity associated to a particular MCR feasible solution. In this work, the two extreme (maximum and minimum) feasible solutions obtained by the MCR-BANDS method are investigated and projected on to the area of feasible solution (AFS) obtained by other methods like the FACPACK method, and compared under the application of different constraints. In contrast to other methods that estimate the whole set of feasible solutions (i.e. the AFS), MCR-BANDS provides a simpler and flexible way to give an estimation of the extension of rotation ambiguity associated to a particular MCR solution (for instance using the MCR-ALS method) of systems with any number of components and under any type of constraints, in the concentration and spectral domains.

UV-vis sensor array combining with chemometric methods for quantitative analysis of binary dipeptide mixture (Gly-Gly/Ala-Gln).

Many endogenous peptides are circulating in bodily fluids at micromole level, and accurate analysis of endogenous peptides at such low level is important. In this study, we presented an extensible, facile and sensitive sensor array based on UV-Vis spectroscopy of the AuNPs combined with chemometric methods for quantitative analysis of binary peptide mixture (Gly-Gly/Ala-Gln) using UV-Vis spectroscopy. High concentration arginine (Arg) and Cr3+ can induce aggregation of the AuNPs and DNA-AuNPs. However, the glycylglycine (Gly-Gly) and alanyl-glutamine (Ala-Gln) can prevent the AuNPs from aggregation. We investigated the prevention of AuNPs aggregation by using Gly-Gly and Ala-Gln mixtures and constructed sensor arrays for quantitative analyses of Gly-Gly and Ala-Gln mixtures. The color change of the solution is relevant to the dose of the target, and it can be visualized by the naked eyes or monitored by UV-Vis spectrometry. Results showed that the concentrations of Arg and Cr3+ are the key factors affecting the sensitivity of the sensor array. Whereas when Gly-Gly and Ala-Gln have to be analyzed simultaneously, concentrations of Arg and Cr3+ both for Gly-Gly and Ala-Gln are difficult to be optimized. Taking the advantages of multivariate analysis and data fusion, PLS models and backward interval PLS (BiPLS) models were built for fused dataset constructed by UV-Vis data obtained at different concentrations of Arg and Cr3+. The best results were obtained from the PLS models. The proposed method can be extended to analysis of other peptides in more complex mixture systems.

A novel systematic absence of cross peaks-based 2D-COS approach for bilinear data.

A novel approach to use two-dimensional correlation spectroscopy (2D-COS) to analyze bilinear data is proposed. A phenomenon called Systematic Absence of Cross Peaks (SACPs) is observed in a 2D asynchronous spectrum. Two theorems relevant to SACPs have been derived. The SACP-based 2D-COS method has been successfully applied on analyzing bilinear data from mixed samples (including one model system and two real systems). Implicit isolated peaks can be identified and assigned to different components based on characteristic pattern of SACPs even if the time-related profiles of different components are severely overlapped. Based on the results of SACPs, spectra of pure components can be retrieved. Identification of SACPs can still be achieved in the presence of artifacts. Thus, neither noise nor baseline drift can produce significant influence on the results obtained from the approach described in this paper. We have used several well-established chemometric methods, including N-Findr, VCA, and MCR with various initial settings, on two systems that can be successfully solved using the 2D-COS method. The chemometric methods mentioned above cannot provide correct spectra of pure components because of severe problem of rotational ambiguity derived from severe overlapping of the time-related profiles. Only when the information from SACPs in 2D-COS is used as additional constraints in MCR calculation, correct spectra can be obtained. That is to say, the SACP-based 2D-COS method provides intrinsic information which is crucial in the analysis of chromatographic-spectroscopic and analogous data even if the time-related profiles of different components overlap severely.

A preliminary study on constructing a high-dimensional asynchronous spectrum to analyze bilinear data.

A novel approach to constructing high-dimensional asynchronous spectra (nD-Asyn) is proposed. Three theorems relevant to 1D slices of nD-Asyn are revealed. nD-Asyn is used to analyze bilinear data from mixtures containing multiple components obtained via hyphenated techniques. The spectral contribution of different components can be removed in a stepwise manner by increasing the dimensions of asynchronous spectra. As a result, the spectra of different components can be faithfully recovered even if the time-related profiles of different components severely overlap. Moreover, correct results can still be obtained via the nD-Asyn even if a considerable level of noise and baseline drift are present. The nD-Asyn approach is compared with MCR-ALS using different constraints in analyzing the data for a simulated and also for a real system. The nD-Asyn produced correct spectrum of every component. Only when complete constraints obtained from nD-Asyn method is utilized in the MCR-ALS calculation, correct spectra of all the components can be obtained. Thus, nD-Asyn can be used alone or in conjunction with MCR-ALS to analyze bilinear data containing contributions of multiple components.

Micelle-Mediated Chemiluminescence as an Indicator for Micellar Transitions.

The structural phase of micelles plays an important role in controlling the micellar performance. Despite the great developments of some advanced characterization techniques, it remains challenging to achieve fast and sensitive determination of micellar transitions in solution. Herein, a novel indicator system for micellar transitions was developed based on the micelle-mediated peroxyoxalate chemiluminescence that showed a sensitive response toward the changes of micellar morphologies. A peroxyoxalate derivative and a fluorophore were first coassembled into the hydrophobic cavities of micelles of the typical cationic surfactant cetyltrimethylammonium bromide (CTAB). A strong and rapidly falling chemiluminescence response was exhibited in spherical micelles as a result of the loose arrangement of CTAB molecules. By contrast, rodlike or wormlike micelles transformed from spherical micelles could induce a compact arrangement of CTAB molecules, leading to a weak chemiluminescence emission with a slow decay rate. The practicability and universality of the chemiluminescent indicator were demonstrated by determining the micellar transitions in a variety of surfactant solutions (ionic, nonionic, and polymeric). These findings open attractive perspectives for the practice of chemiluminescence technique in micelle characterization.

Synthesis, Anti-Varicella-Zoster Virus and Anti-Cytomegalovirus Activity of 4,5-Disubstituted 1,2,3-(1H)-Triazoles.

BACKGROUND: Clinical drugs for herpesvirus exhibit high toxicity and suffer from significant drug resistance. The development of new, effective, and safe anti-herpesvirus agents with different mechanisms of action is greatly required. OBJECTIVE: Novel inhibitors against herpesvirus with different mechanisms of action from that of clinical drugs. METHODS: A series of novel 5-(benzylamino)-1H-1,2,3-triazole-4-carboxamides were efficiently synthesized and EC50 values against Human Cytomegalovirus (HCMV), Varicella-Zoster Virus (VZV) and Herpes Simplex Virus (HSV) were evaluated in vitro. RESULTS: Some compounds present antiviral activity. Compounds 5s and 5t are potent against both HCMV and VZV. Compounds 5m, 5n, 5s, and 5t show similar EC50 values against both TK+ and TK- VZV strains. CONCLUSION: 5-(Benzylamino)-1H-1, 2,3-triazole-4-carboxamides are active against herpesviruses and their activity is remarkably affected by the nature and the position of substituents in the benzene ring. The results indicate that these derivatives are independent of the viral thymidine kinase (TK) for activation, which is indispensable for current drugs. Their mechanisms of action may differ from those of the clinic anti-herpesvirus drugs.

Sensor array for qualitative and quantitative analysis of metal ions and metal oxyanion based on colorimetric and chemometric methods.

Gold nanoparticle (AuNP)-based colorimetric sensor is sensitive for the detection of metal ions and metal oxyanion in aqueous solution. However, this method is usually not suitable for multi-objective analysis in complex mixture systems because it is suffering from interference of co-existents. In the present paper, we proposed a sensitive, flexible, low-cost, and multi-units sensor method for the qualitative and quantitative analysis of metal ions and metal oxyanion based on the global ultraviolet and visible (UV-Vis) spectra of amino acid-gold nanoparticles (amino acid-AuNPs) sensors in the range of 230-800 nm. Different amino acids (L-Histidine, L-Lysine, L-Methionine, D-Penicillium) which can prevent the aggregation of the AuNPs in NaCl solution, were investigated to build sensor arrays responding to different ions induced AuNPs aggregation. The UV-Vis spectra that Cd2+, Ba2+, Mn2+, Ni2+, Cu2+, Fe3+, Cr3+, Cr2O72-, Sn4+, Pb2+ induce amino acid-AuNPs displayed different characteristics and the ions were classified correctly by using partial least squares-discriminant analysis (PLS-DA). Taking the advantage of the multivariate analysis and sensor arrays, we simultaneously quantified the ions in binary and ternary mixture systems (Cr3+/Cr2O72-, Fe3+/Cd2+, Fe3+/Cr3+/Cr2O72-). Data fusion methods further improved the prediction accuracy of the chemometric models built on multi-amino acids-AuNPs sensors. The proposed method has a potential for analyzing metal ions and metal oxyanion in much more complex mixture systems.

Synthesis and Ativiral Activity of 5-(Benzylthio)-4-carbamyl-1,2,3-triazoles Against Human Cytomegalovirus (CMV) and Varicella-zoster Virus (VZV).

BACKGROUND: All of the clinical drugs for herpesvirus infections exhibit high toxicity and suffer from significant drug-resistantance. There is a great need for the development of new, effective, and safe anti-herpesvirus agents with different mechanisms of action. METHODS: A series of novel 5-(benzylthio)-1H-1,2,3-triazole-4-carboxamides were efficiently synthesized and EC50 values against human cytomegalovirus (HCMV), varicella-zoster virus (VZV) and herpes simplex virus (HSV) were evaluated in vitro. RESULTS: Some compounds possess antiviral activity. Compound 7f exhibits promising inhibitory activity against both HCMV and VZV. Our results also indicate that these derivatives are independent of the viral thymidine kinase (TK) for activation, which is indispensable for current drugs. CONCLUSION: 4,5-Bissubstiuted triazoles are active against herpesviruses and the nature and the position of substituents in the benzene ring remarkably affect their activity, such as bromo, cyano and cyanovynil substituents. Future studies should be undertaken to investigate the mechanism of action of these compounds.

Data fusion of near-infrared and mid-infrared spectra for identification of rhubarb.

Rhubarb has different medicinal efficacy to official rhubarb and may affect the clinical medication safety. In order to guarantee the quality of rhubarb, we established a method to distinguish unofficial rhubarbs. 52 official and unofficial rhubarb samples were analyzed using near-infrared (NIR) spectroscopy and mid-infrared (MIR) spectroscopy for classification. The feature vectors, which were selected by wavelet compression (WC) and interval partial least squares (iPLS) from NIR, MIR spectra, were fused together for identifying rhubarb samples. Partial least squares-discriminant analysis (PLS-DA), soft independent modeling of class analogies (SIMCA), support vector machine (SVM) and artificial neural network (ANN) were compared for classifying rhubarb. The use of data fusion strategies improved the classification model and allowed correct classification of all the samples.

Clinical risk assessment of patients with chronic kidney disease by using clinical data and multivariate models.

PURPOSE: Timely risk assessment of chronic kidney disease (CKD) and proper community-based CKD monitoring are important to prevent patients with potential risk from further kidney injuries. As many symptoms are associated with the progressive development of CKD, evaluating risk of CKD through a set of clinical data of symptoms coupled with multivariate models can be considered as an available method for prevention of CKD and would be useful for community-based CKD monitoring. METHODS: Three common used multivariate models, i.e., K-nearest neighbor (KNN), support vector machine (SVM), and soft independent modeling of class analogy (SIMCA), were used to evaluate risk of 386 patients based on a series of clinical data taken from UCI machine learning repository. Different types of composite data, in which proportional disturbances were added to simulate measurement deviations caused by environment and instrument noises, were also utilized to evaluate the feasibility and robustness of these models in risk assessment of CKD. RESULTS: For the original data set, three mentioned multivariate models can differentiate patients with CKD and non-CKD with the overall accuracies over 93 %. KNN and SVM have better performances than SIMCA has in this study. For the composite data set, SVM model has the best ability to tolerate noise disturbance and thus are more robust than the other two models. CONCLUSIONS: Using clinical data set on symptoms coupled with multivariate models has been proved to be feasible approach for assessment of patient with potential CKD risk. SVM model can be used as useful and robust tool in this study.

Quantitative measurements of binary amino acids mixtures in yellow foxtail millet by terahertz time domain spectroscopy.

Terahertz time domain spectroscopy (THz-TDS) combined with chemometrics has been utilized for the qualitative and quantitative analysis of binary mixtures of l-glutamic acid and l-glutamine which have similar chemical structures and properties. The binary mixtures of amino acids were prepared with yellow foxtail millet matrix, substituted for polyethylene (PE) as previously reported. After proper pretreatment of absorption spectra, quantitative analysis was achieved by partial least squares (PLS) and interval partial least squares (iPLS) regressions. The performance of models was evaluated based on the root mean square error of prediction (RMSEP) and correlation coefficient (R(2)) of cross-validations with bootstrapped Latin partitions as criterion. The iPLS yielded better results with low RMSEP (0.39±0.02%, 0.39±0.02%), and higher R(2) values (0.9904, 0.9906) for glutamine and glutamic acid comparing to the conventional PLS models. Multivariate curve resolution alternating least squares (MCR-ALS) was successfully applied for resolution of pure THz spectra and concentration profiles of two amino acids components from mixtures.

[Identification of Official Rhubarb Samples by Using PLS and Terahertz Time-Domain Spectroscopy].

The development of terahertz technology is attracting broad intention in recent years. The quality identification is important for the quality control of Chinese medicine production. In the present work, terahertz time-domain spectroscopy (THz-TDS) combined with partial least squares (PLS) were used for the identification model building and studied based on 41 official and unofficial rhubarb samples. First, the THz-TDS spectra of rhubarb samples were collected and were preprocessed by using chemometrics methods rather than transformed to absorption spectra. The identification models were then established based on the processed terahertz time domain spectra. The spectral preprocessing methods include Savitzky-Golay (S-G) first derivative, detrending, standard normal transformation (SNV), autoscaling, and mean centering. The identification accuracy of 90% was accomplished by using proper pretreatment methods, which was higher than the classified accuracy of 80% without any preprocessing for the time domain spectra. The component number of the PLS model was evaluated by leave-one-out cross-validation (LOOCV). The minimum values of the root-mean squared error of cross-validation (RMSECV) and root-mean squared error of prediction (RMSEP) were 0.076 6 and 0.169 0 by using mean centering method, respectively. The results of this work showed that the combination of terahertz time domain spectroscopy technology with chemometrics methods, as well as PLS can be applied for the recognition of genuine and counterfeit Chinese herbal medicines, as well as official and unofficial rhubarbs. The advantage of using terahertz time domain spectra directly with no transformation into absorption spectra is: (1) the thickness of samples could not be considered in the model establishment, and (2) the spectral processing was simplified. The proposed method based on the combination of THz-TDS and chemometrics proved to be rapid, simple, non-pollution and solvent free, suitable to be developed as a promising tool for quality control of many other Chinese herbal medicines.

[Determination of Carbaryl in Rice by Using FT Far-IR and THz-TDS Techniques].

Determination of carbaryl in rice by using Fourier transform far-infrared (FT- Far-IR) and terahertz time-domain spectroscopy (THz-TDS) combined with chemometrics was studied and the spectral characteristics of carbaryl in terahertz region was investigated. Samples were prepared by mixing carbaryl at different amounts with rice powder, and then a 13 mm diameter, and about 1 mm thick pellet with polyethylene (PE) as matrix was compressed under the pressure of 5-7 tons. Terahertz time domain spectra of the pellets were measured at 0.5~1.5 THz, and the absorption spectra at 1.6. 3 THz were acquired with Fourier transform far-IR spectroscopy. The method of sample preparation is so simple that it does not need separation and enrichment. The absorption peaks in the frequency range of 1.8-6.3 THz have been found at 3.2 and 5.2 THz by Far-IR. There are several weak absorption peaks in the range of 0.5-1.5 THz by THz-TDS. These two kinds of characteristic absorption spectra were randomly divided into calibration set and prediction set by leave-N-out cross-validation, respectively. Finally, the partial least squares regression (PLSR) method was used to establish two quantitative analysis models. The root mean square error (RMSECV), the root mean square errors of prediction (RMSEP) and the correlation coefficient of the prediction are used as a basis for the model of performance evaluation. For the R,, a higher value is better; for the RMSEC and RMSEP, lower is better. The obtained results demonstrated that the predictive accuracy of. the two models with PLSR method were satisfactory. For the FT-Far-IR model, the correlation between actual and predicted values of prediction samples (Rv) was 0.99. The root mean square error of prediction set (RMSEP) was 0.008 6, and for calibration set (RMSECV) was 0.007 7. For the THz-TDS model, R. was 0. 98, RMSEP was 0.004 4, and RMSECV was 0.002 5. Results proved that the technology of FT-Far-IR and THz- TDS can be a feasible tool for quantitative determination of carbaryl in rice. This paper provides a new method for the quantitative determination pesticide in other grain samples.

Fluorescence spectroscopy and molecular simulation on the interaction of caffeic acid with human serum albumin.

Fluorescence spectroscopy and molecular simulation were explored to study the interaction between caffeic acid and human serum albumin (HSA). The experimental results indicated that the fluorescence quenching mechanism between caffeic acid and HSA is a static quenching, which was proved again by the analysis of fluorescence lifetime by time-correlated single photon counting. The binding process is spontaneous and the hydrophobic force is the main force between caffeic acid and HSA. In addition, the binding of caffeic acid to HSA was modeled by molecular dynamics simulations. The root mean square deviations, root mean square fluctuations, radius of gyration and the number of hydrogen bonds of the molecular dynamic (MD) simulation process were analyzed. Both experimental and modeling results demonstrated strong binding between HSA and caffeic acid. HSA had a slight conformational change when it binds with caffeic acid. The obtained information is useful for HSA drug design. Copyright © 2016 John Wiley & Sons, Ltd.

Synthesis and Bioactivity of Novel Trisubstituted Triazole Nucleosides.

A series of novel trisubstituted 1,2,3-triazole purine nucleosides were efficiently synthesized via Huisgen 1,3-dipolar cycloaddition in good yields. Bioactivity against cytomegalovirus (CMV) and varicella-zoster virus (VZV) in human embryonic lung cell cultures was evaluated and all compounds show low antiviral activity.

[Studies on Cancer Diagnosis by Using Spectroscopy Combined with Chemometrics].

Studies on cancer diagnosis using various spectroscopic methods combined with chemometrics are briefly reviewed. Elemental contents in serum samples were determined by inductively coupled plasma atomic emission spectroscopy (ICP-AES), bidirectional associative memory (BAM) networks were used to establish diagnosis models for the relationships between elemental contents and lung cancer, liver cancer, and stomach cancer, respectively. Near infrared spectroscopy (NIRS) is a non-destructive detection technology. Near infrared spectra of endometrial carcinoma samples were determined and spectral features were extracted by chemoometric methods, a fuzzy rule-based expert system (FuRES) was used for establishing diagnosis model, satisfactory results were obtained. We also proposed a novel variable selection method based on particle swarm optimization (PSO) for near infrared spectra of endometrial carcinoma samples. Spectra with optimized variable were then modeled by support victor machine (SVM). Terahertz technology is an emerging technology for non-destructive detection, which has some unique characteristics. Terahertz time domain spectroscopy (THz-TDS) was used for cervical carcinoma measurement. Absorption coefficients were calculated from the measured time domain spectra and then processed with derivative, orthogonal signal correction (PC-OSC) to reduce interference components, and then fuzzy rule-based expert system (FuRES), fuzzy optimal associative memory (FOAM), support victor machine (SVM), and partial least squares discriminant analysis (PLS-DA) were used for diagnosis model establishment. The above results provide useful information for cancer occurring and development, and provide novel approaches for early stage diagnosis of various cancers.

[A Terahertz Spectral Database Based on Browser/Server Technique].

With the solution of key scientific and technical problems and development of instrumentation, the application of terahertz technology in various fields has been paid more and more attention. Owing to the unique characteristic advantages, terahertz technology has been showing a broad future in the fields of fast, non-damaging detections, as well as many other fields. Terahertz technology combined with other complementary methods can be used to cope with many difficult practical problems which could not be solved before. One of the critical points for further development of practical terahertz detection methods depends on a good and reliable terahertz spectral database. We developed a BS (browser/server) -based terahertz spectral database recently. We designed the main structure and main functions to fulfill practical requirements. The terahertz spectral database now includes more than 240 items, and the spectral information was collected based on three sources: (1) collection and citation from some other abroad terahertz spectral databases; (2) collected from published literatures; and (3) spectral data measured in our laboratory. The present paper introduced the basic structure and fundament functions of the terahertz spectral database developed in our laboratory. One of the key functions of this THz database is calculation of optical parameters. Some optical parameters including absorption coefficient, refractive index, etc. can be calculated based on the input THz time domain spectra. The other main functions and searching methods of the browser/server-based terahertz spectral database have been discussed. The database search system can provide users convenient functions including user registration, inquiry, displaying spectral figures and molecular structures, spectral matching, etc. The THz database system provides an on-line searching function for registered users. Registered users can compare the input THz spectrum with the spectra of database, according to the obtained correlation coefficient one can perform the searching task very fast and conveniently. Our terahertz spectral database can be accessed at http://www.teralibrary.com. The proposed terahertz spectral database is based on spectral information so far, and will be improved in the future. We hope this terahertz spectral database can provide users powerful, convenient, and high efficient functions, and could promote the broader applications of terahertz technology.

Terahertz time-domain spectroscopy combined with fuzzy rule-building expert system and fuzzy optimal associative memory applied to diagnosis of cervical carcinoma.

Combined with terahertz time-domain spectroscopy, the feasibility of fast and reliable diagnosis of cervical carcinoma by a fuzzy rule-building expert system (FuRES) and a fuzzy optimal associative memory (FOAM) had been studied. The terahertz spectra of 52 specimens of cervix were collected in the work. The original data of samples were preprocessed by Savitzky-Golay first derivative (χderivative), principal component orthogonal signal correction (PC-OSC) and emphatic orthogonal signal correction to improve the performance of FuRES and FOAM models. The effect of the different pretreating methods to improve prediction accuracy was evaluated. The FuRES and FOAM models were validated using bootstrapped Latin-partition method. The obtained results showed that the FuRES and FOAM model optimized with the combination S-G first derivative and PC-OSC method had the better predictive ability with classification rates of 92.9 ± 0.4 and 92.5 ± 0.4 %, respectively. The proposed procedure proved that terahertz spectroscopy combined with fuzzy classifiers could supply a technology which has potential for diagnosis of cancerous tissue.

Topomer CoMFA and virtual screening studies of azaindole class renin inhibitors.

Direct renin inhibitors (DRIs) have increasingly shown a significant advantage in the treatment of hypertension and protection of target organs. In this paper, a series of azaindole class renin inhibitors were subjected to 3D-QSAR study using Topomer CoMFA. Five kinds of splitting mode for different fragment cutting and 6 different training and test sets grouping were attempted to build consensus models. The results indicated that 6 consensus models had similar predictability (q(2) and r(2) pred) and stability (r(2)). The best model showed good stability and predictability (q(2) of 0.616, r(2) of 0.908). The r(2) pred value of the external test set was 0.70, which means that the model had an excellent external predictive ability, and the robustness of the developed model was assessed by the Y-randomization test. This study also adopted the methodology of fragment-based drug design (FBDD) to virtual screen new renin inhibitors by using Topomer Search technology. The R1-group of the compound No. 13 with the highest activity was chosen as the basic scaffold, and its remaining R2-group acted as a query to screen 142,025 molecules of ZINC database for similar fragments. The obtained 30 fragments with the highest R2-group contribution values were added to the basic scaffold respectively. Finally 30 new azaindole compounds with potent high activities were obtained. Further the binding modes were studied by using Surflex- Dock. The docking results showed good binding interactions of the designed compounds with the renin protein, thus the rationality of this design was further verified from the perspective of the renin receptor.