3D-QSARpy: Combining variable selection strategies and machine learning techniques to build QSAR models

Abstract Quantitative Structure-Activity Relationship (QSAR) is a computer-aided technology in the field of medicinal chemistry that seeks to clarify the relationships between molecular structures and their biological activities. Such technologies allow for the acceleration of the development of new compounds by reducing the costs of drug design. This work presents 3D-QSARpy, a flexible, user-friendly and robust tool, freely available without registration, to support the generation of QSAR 3D models in an automated way. The user only needs to provide aligned molecular structures and the respective dependent variable. The current version was developed using Python with packages such as scikit-learn and includes various techniques of machine learning for regression. The diverse techniques employed by the tool is a differential compared to known methodologies, such as CoMFA and CoMSIA, because it expands the search space of possible solutions, and in this way increases the chances of obtaining relevant models. Additionally, approaches for select variables (dimension reduction) were implemented in the tool. To evaluate its potentials, experiments were carried out to compare results obtained from the proposed 3D-QSARpy tool with the results from already published works. The results demonstrated that 3D-QSARpy is extremely useful in the field due to its expressive results.

Insight into DNA Gyrase inhibition using quantitative structure-Activity relationships and structure-based drug design approaches

The emergence of certain bacterial strains resistant to antibiotics has become a major public health problem, hence the need to develop new antibiotic molecules. Bacterial DNA gyrase, a type II DNA topoisomerase found in all bacteria is a proven target for antibacterial chemotherapy. Our objective is designing novel DNA Gyrase inhibitors using Quantitative StructureActivity Relationships and Structure-Based Drug Design Approaches. We used bioinformatics tools, biological databases like PDB (Protein DataBank), Binding Databases and software's like, MarvinView, MarvinSketch, PyMOL, AutoDockTools-1.5.6. The 3D crystal structure of DNA Gyrase was extracted from PDB (code: 4DHU) and we characterized the active site. Using 83 compounds with different Ki were extracted from Binding Databases, we built and validated a QSAR Model (PLS regression) and we confirmed the interesting correlation between predicted and experimental Ki (R2=0,843). Four molecules were chosen to be docked into DNA Gyrase active site using AutoDockTools. The compound which has the low Ki (Benzimidazole urea analogue 5) shows more binding affinity with score value of ΔG= -8,6 kcal/mol than the others compounds. So, it would be very interesting to synthesis this promising compound and to test in vitro its antibacterial properties.

Applications of QSAR in Toxicological Risk Assessment of Medical Devices / 中国医疗器械杂志

The chemical characterization analysis of a medical device often results in chemical substances with unknown toxicities. While identification of each individual toxicity could result in a time-consuming hurdle with tremendous labor and financial burden, quantitative structure-activity relationship (QSAR) is of great significance for toxicity risk assessment of such chemical substances. By establishing quantitative relationship between the molecular structures or active groups of similar chemical compounds with their biological activities, QSAR can be utilized to predict the toxicity of such target compounds with significantly reduced cost and time. In this article, the authors generally summarized the mechanisms of QSAR approaches, current applications of QSAR modeling in the field of medical device, an introduction of the characteristics of publicly and commercially-available QSAR software, and briefly explored future trends of QSAR modeling in medical device toxicological risk assessment. The utilization of QSAR would undoubtedly further advance the toxicological risk assessment of medical devices.

Natural radioprotectors and their impact on cancer drug discovery

Cancer is a complex multifaceted illness that affects different patients in discrete ways. For a number of cancers the use of chemotherapy has become standard practice. Chemotherapy is a use of cytostatic drugs to cure cancer. Cytostatic agents not only affect cancer cells but also affect the growth of normal cells; leading to side effects. Because of this, radiotherapy gained importance in treating cancer. Slaughtering of cancerous cells by radiotherapy depends on the radiosensitivity of the tumor cells. Efforts to improve the therapeutic ratio have resulted in the development of compounds that increase the radiosensitivity of tumor cells or protect the normal cells from the effects of radiation. Amifostine is the only chemical radioprotector approved by the US Food and Drug Administration (FDA), but due to its side effect and toxicity, use of this compound was also failed. Hence the use of herbal radioprotectors bearing pharmacological properties is concentrated due to their low toxicity and efficacy. Notably, in silico methods can expedite drug discovery process, to lessen the compounds with unfavorable pharmacological properties at an early stage of drug development. Hence a detailed perspective of these properties, in accordance with their prediction and measurement, are pivotal for a successful identification of radioprotectors by drug discovery process.

Determination of the total phenolic, flavonoid and antioxidant activity of Sabalan Honey

Background: Honey is recognized as having different biological properties including antioxidant effects. Phenolic acids and flavonoids are the main antioxidant in this apiary product

Objectives: In this study eight samples of Sabalan honey were screened to evaluate the antioxidant activity, total phenolic and flavonoid content

Methods: Antioxidant activity of honey samples was determined by DPPH [2,2-diphenyl-l-picryl hydrazyl] method and p-carotene bleaching assay, total phenolic and flavonoid by Folin-Ciocalteu and Aluminium chloride methods, in addition, in all samples, some physico-chemical parameters [pH, acidity, diastase activity, existence or nonexistence of HMF] were measured according to Iranian National Standardization N92. Data were analyzed using ANOVA [one-way]

Results: Total phenolic and flavonoid content of honeys ranged respectively from 15.71- 41.58 [mg GAE/l00g honey] and 3.80-13.20 [mg QE/100g honey]. Antioxidant activity was between 23.19%-94.25%, p-carotene bleaching inhibition 69.54%-85.69%, pH ranged from 3.63-3.83, Acidity 11.99-20.50 mEq/kg, diastase activity of all samples was negative except sample No. 1. All samples had positive HMF results

Conclusions: Regarding the above results, it could be concluded that the honey samples have significant antioxidant activity. All parameters of physicochemical test were according to the international specifications except diastase and HMF tests, which may be due to improper processing and storage condition, heating treatment, old honey,etc.

Synthesis, antileishmanial activity and QSAR studies of 2-chloro- N -arylacetamides

ABSTRACT We describe herein the synthesis and evaluation of the antileishmanial activity against promastigote forms of Leishmania amazonensis and cytotoxicity to murine macrophages of a series of 2-chloro-N-arylacetamide derivatives. All compounds were active, except one (compound 3). Compound 5 presented the most promising results, showing good antileishmanial activity (CI50=5.39±0.67 µM) and moderate selectivity (SI=6.36), indicating that further development of this class is worthwhile. Preliminary QSAR studies, although not predictive, furnished some insights on the importance of electronic character of aryl substituent to biological activity, as well as an indirect influence of hydrophobicity on activity.

Investigação oftalmológica pré-clínica do óleo essencial de Origanum vulgare L. Lamiaceae / Ophthalmological pre-clinical research about essential oil from the Origanum vulgare L. Lamiaceae

RESUMO Objetivo: Avaliar a irritação ocular aguda em coelhos, após a administração tópica de óleo essencial. Métodos: Para tanto, os animais foram divididos em três grupos, cada um com três coelhos, totalizando 6 olhos por grupo, e a diferença entre eles foi a concentração utilizada ( 1, 3 e 9%). Aplicou-se no saco conjuntival, de um dos olhos do animal, uma dose única de 0,1 ml do produto e o olho contralateral foi usado como controle. Analisou-se os efeitos causados pelo óleo essencial na conjuntiva, íris e córnea após 1, 24, 48, 72 horas e no final do sétimo dia após a aplicação tópica. As avaliações oftalmológicas foram feitas com o auxílio de um oftalmoscópio binocular indireto com e sem fluoresceína. As reações observadas foram graduadas segundo a escala de Draize. Foram realizados exames anatomopatológicos em todos os olhos estudados no final do experimento. Resultados: No grupo de animais submetidos à instilação ocular do óleo essencial a 1%, não se observou alterações. O tratamento com o óleo a 3% provocou alteração conjuntival no exame feito em 1 hora, o que foi reduzindo. A administração do óleo essencial a 9% induziu hiperemia conjuntival, não havendo qualquer alteração nos outros tempos de avaliação oftalmológica. Conclusão: A avaliação contribuiu para conhecer as alterações clínicas na superfície ocular. Desta forma, foi possível classificar o óleo a 1% como não irritante e nas concentrações de 3 e 9% como pouco irritante, tornando possível estudos clínicos, a fim de estabelecer o óleo como alternativa terapêutica em conjuntivites bacterianas.

ABSTRACT Objective: To evaluate acute eye irritation in rabbits following topical administration of essential oil. Methods: animals were divided into three groups, each containing three rabbits, with a total of 6 eyes per group. The difference between them was the concentration used (1, 3 and 9%). A single dose of 0.1 ml of the product was applied into the conjunctival sac of one eye of the animal, and the contralateral eye was used as control. The effects caused by the essential oil in the conjunctiva, iris and cornea were analyzed after 1, 24, 48 and 72 hours and at the end of the seventh day after topical application. Ophthalmologic evaluations were performed with the aid of a binocular indirect ophthalmoscope fluorescein and with and without the observed responses, before being graded according to the Draize scale. Pathological examinations were performed on all eyes studied at the end of the experiment. Results: in the group of animals subjected to the ocular instillation of 1% essential oil, there was no change. For treatment with 3% oil, conjunctival changes were found to be decreasing during the examination after 1 hour. Administration of the 9%essential oil induced conjunctival injection, without any change in the other ophthalmologic evaluation times. Conclusion: the evaluation contributed to meet the clinical changes in the ocular surface. Thus, it was possible to classify the oil at 1% as non-irritating and the concentration of 3% and 9 as mildly irritating, making it possible for clinical studies to establish the oil as an alternative therapy in bacterial conjunctivitis.

Planejamento de fármacos anti-T. cruzi: Síntese de compostos nitrofurânicos, avaliação da atividade biológica in vitro e estudos de relações estrutura-atividade / Design of anti-T. cruzi compounds: Synthesis of 5-nitrofuran derivatives, in vitro biological activity and study of structure-activity relationships

A doença de Chagas afeta cerca de 6 a 7 millhões de pessoas no mundo, principalmente América Latina. A busca de alternativas terapêuticas para esta enfermidade tem grande relevância para a sociedade, já que as opções atuais são limitadas, sendo disponível apenas o benznidazol (BZD) e nifurtimox. Os derivados nitroheterocíclicos são considerados compostos bioativos com número crescente de estudos na comunidade científica contra seu agente etiológico, o Trypanosoma cruzi. Neste sentido, o presente trabalho tem por objetivo a identificação de derivados do 5-nitrofurano com atividade frente a diferentes cepas do T. cruzi, assim como estudar possíveis modo de ação desta classe de compostos. Esta investigação envolve estudos computacionais com o propósito de construir modelos quantitativos de relações estrutura-atividade (QSAR multivariado) que possam auxiliar na previsão de novas estruturas com perfil farmacológico otimizado. No presente trabalho foram realizadas as etapas de planejamento, síntese e identificação de 36 compostos com resultados satisfatórios quanto à identificação estrutural, pureza e rendimento, que foi da ordem de 70%. A determinação da atividade anti-T. cruzi in vitro dos compostos obtidos foi realizada frente às cepas Silvio X10 cl1, Y, Bug 2149 cl10 e Colombiana na forma epimastigota do parasito. A maioria dos compostos analisados apresentou maior capacidade de inibição de crescimento do parasito, comparado ao BZD: Silvio X10 cl1 - IC50 = 29,16 ±2,90 µM, Y - IC50 = 40,40 ±3,37µM, Bug 2149 cl10 - IC50 = 30,63 ±3,21 µM, Colombiana - IC50 = 47,91 ±4,96 µM. O composto mais ativo (BSF-35) apresentou os seguintes valores: Silvio X10 cl1 - IC50 = 3,17 ±0,32 µM, Y - IC50 = 1,17 ±0,12 µM, Bug 2149 cl10 - IC50 = 1,81 ±0,18 µM e Colombiana - IC50 = 3,06 ±0,23 µM. Foram realizados cálculos de propriedades moleculares das estruturas tridimensionais dos compostos, seguido pela análise exploratória de dados por análise de agrupamentos hierárquicos (HCA) e análise de componentes principais (PCA), possibilitando o reconhecimento de padrões do conjunto. Considerando esta análise prévia, foram obtidos modelos QSAR com abordagem multivariada, aplicando algorítmo OPS e método de regressão por quadrados mínimos parciais, PLS. Os melhores modelos gerados foram obtidos considerando os compostos benzenos substituídos para as quatro cepas estudadas. Os descritores que mais influenciaram na análise foram o ClogP (coeficiente de partição) e cargas CHELPG. Considerando as informações obtidas, foram planejados e sintetizados quatro novos compostos com objetivo de obter compostos mais ativos e validar os modelos QSAR. Estes compostos apresentaram alta atividade frente a forma epimastigota das quatro cepas estudadas. Os compostos mais ativos foram avaliados quanto a citotoxicidade frente células LLC-MK2 e apresentaram seletividade até 25 vezes superior ao BZD. Estudos in vitro frente a forma amastigota da cepa Y em células U2OS foram realizados com metodologia fenotípica de análise de alto conteúdo (HCA') e os compostos apresentaram atividade até 64 vezes superior ao BZD e com seletividade de até 50 vezes superior a este fármaco. Quanto à determinação da atividade dos compostos frente às enzimas tripanotiona redutase (TcTR) e glutationa redutase (GR), os compostos analisados não apresentaram atividade relevante, indicando não ser este o mecanismo desta classe de compostos. Com finalidade de explorar outro possível mecanismo de ação dos compostos 5-nitrofurânicos, foi realizada a análise de potencial de redução da membrana mitocondrial, porém a morte parasitária não foi atribuída à despolarização da membrana em estudos simultâneos com iodeto de propídio

Chagas disease affects approximately 6-7 millions people worldwide, especially Latin America. The search for therapeutic alternatives for this disease is of great relevance to society, as current options are limited and there are only two available drugs: benznidazole (BZD) and nifurtimox. The nitroheterocyclic derivatives are considered bioactive compounds with increasing number of studies in the scientific community against its etiologic agent, Trypanosoma cruzi. In this sense, this work aims to identify derivatives of 5-nitrofuran with activity against different strains of T. cruzi, and to study possible mode of action of this compounds. This research involves computational studies to obtain models of quantitative structure-activity relationships (QSAR multivariate) that can help predict new structures with optimized pharmacological profile. In this work were carried out the design, synthesis and identification of 36 compounds with satisfactory results regarding the structural identification, purity and yield (approximately 70%). The determination of anti-T. cruzi activity in vitro of the compounds obtained was carried out with Silvio X10 cl1, Y, Bug 2149 CL10 and Colombiana strains of epimastigote form of the parasite. Most of the compounds examined showed greater capacity of growth inhibition of the parasite compared to the BZD (Silvio X10 CL1 - IC 50 = 29.16 ± 2.90 µM, Y - IC50 = 40.40 ± 3,37µM, 2149 CL10 Bug - IC 50 = 30.63 ± 3.21 µM, Colombiana - IC 50 = 47.91 ± 4.96 µM). The most active compound (BSF-35) showed the following values: Silvio X10 cl1 - IC 50 = 3.17 ± 0.32 uM, Y - IC 50 = 1.17 ± 0.12 µM, Bug 2149 CL10 - IC50 = 1, 81 ± 0.18 µM and Colombiana - IC 50 = 3.06 ± 0.23 µM. Calculations were performed for the molecular properties of three-dimensional structures of the compounds, followed by exploratory data analysis by hierarchical cluster analysis (HCA) and principal component analysis (PCA), allowing the recognition of the set. Considering this preliminary analysis were obtained QSAR models with multivariate approach, using OPS algorithm and regression method of partial least squares, PLS. The best generated models were obtained considering the benzyl substituted compounds for the four strains. The descriptors that most influenced the analysis were ClogP (partition coefficient) and CHELPG charges. Considering the information obtained, four new compounds were designed and synthesized to obtain more active compounds and validate QSAR models. These compounds showed high activity against epimastigote form of the four strains studied. The most active compounds were evaluated for cytotoxicity against LLC-MK2 cells and the compounds selectivity values were up to 25 times higher than BZD. In vitro studies against amastigote form of the Y strain in U2OS cells were performed with phenotypic method of high content analysis (HCA') and the compounds showed activity to 64 times higher than BZD and selectivity of up to 50 times. The activity of the compounds against trypanothione reductase enzymes (TcTR) and glutathione reductase (GR) showed no significant activity, indicating that this is not the mechanism of this class of compounds. In order to exploit another possible mechanism of action of 5-nitrofuran derivatives, analysis reduction of mitochondrial membrane potential was held, however the cell death was not attributed to membrane depolarization in simultaneous studies with propidium iodide

In silico investigation of agonist activity of a structurally diverse set of drugs to hPXR using HM-BSM and HM-PNN / 华中科技大学学报（医学）（英德文版）

The human pregnane X receptor (hPXR) plays a critical role in the metabolism, transport and clearance of xenobiotics in the liver and intestine. The hPXR can be activated by a structurally diverse of drugs to initiate clinically relevant drug-drug interactions. In this article, in silico investigation was performed on a structurally diverse set of drugs to identify critical structural features greatly related to their agonist activity towards hPXR. Heuristic method (HM)-Best Subset Modeling (BSM) and HM-Polynomial Neural Networks (PNN) were utilized to develop the linear and non-linear quantitative structure-activity relationship models. The applicability domain (AD) of the models was assessed by Williams plot. Statistically reliable models with good predictive power and explain were achieved (for HM-BSM, r (2)=0.881, q LOO (2) =0.797, q EXT (2) =0.674; for HM-PNN, r (2)=0.882, q LOO (2) =0.856, q EXT (2) =0.655). The developed models indicated that molecular aromatic and electric property, molecular weight and complexity may govern agonist activity of a structurally diverse set of drugs to hPXR.

Computational drug design strategies applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors

Reverse transcriptase (RT) is a multifunctional enzyme in the human immunodeficiency virus (HIV)-1 life cycle and represents a primary target for drug discovery efforts against HIV-1 infection. Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs) and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs. However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents. Computational methods are a significant part of the drug design process and indispensable to study drug resistance. In this review, recent advances in computer-aided drug design for the rational design of new compounds against HIV-1 RT using methods such as molecular docking, molecular dynamics, free energy calculations, quantitative structure-activity relationships, pharmacophore modelling and absorption, distribution, metabolism, excretion and toxicity prediction are discussed. Successful applications of these methodologies are also highlighted.

QSAR study on anti-HIV-1 activity of 4-Oxo-1,4-dihydroquinoline and 4-Oxo-4H-pyrido[1,2-a]pyrimidine derivatives using SW-MLR, artificial neural network and filtering methods

Predictive quantitative structure-activity relationship was performed on the novel4-oxo-1,4-dihydroquinoline and 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives to explore relationship between the structure of synthesized compounds and their anti-HIV-1 activities. In this way, the suitable set of the molecular descriptors was calculated and the important descriptors using the variable selections of the stepwise technique were selected. Multiple linear regression [MLR] and artificial neural network [ANN] as nonlinear system were used for constructing QSAR models. The predictive quality of the quantitative structure-activity relationship models was tested for an external set of five compounds, randomly chosen out of 25 compounds. The findings exhibited that stepwise-ANN model was more efficient at prediction activity of both training and test sets with high statistical qualities. Based on QSAR models results, electronegativity, the atomic masses, the atomic van der Waals volumes, the molecular symmetry and polarizability were found to be important factors controlling the anti-HIV-1 activity

Quantitative structure characteristics and fractal dimension of Chinese medicine granules measured by synchrotron radiation X-ray computed micro tomography / 药学学报

The shape and structure of granules are controlled by the granulation process, which is one of the main factors to determine the nature of the solid dosage forms. In this article, three kinds of granules of a traditional Chinese medicine for improving appetite and promoting digestion, namely, Jianwei Granules, were prepared using granulation technologies as pendular granulation, high speed stirring granulation, and fluidized bed granulation and the powder properties of them were investigated. Meanwhile, synchrotron radiation X-ray computed micro tomography (SR-µCT) was applied to quantitatively determine the irregular internal structures of the granules. The three-dimensional (3D) structure models were obtained by 3D reconstruction, which were more accurately to characterize the three-dimensional structures of the particles through the quantitative data. The models were also used to quantitatively compare the structural differences of granules prepared by different granulation processes with the same formula, so as to characterize how the production process plays a role in the pharmaceutical behaviors of the granules. To focus on the irregularity of the particle structure, the box counting method was used to calculate the fractal dimensions of the granules. The results showed that the fractal dimension is more sensitive to reflect the minor differences in the structure features than the conventional parameters, and capable to specifically distinct granules in structure. It is proved that the fractal dimension could quantitatively characterize the structural information of irregular granules. It is the first time suggested by our research that the fractal dimension difference (Df,c) between two fractal dimension parameters, namely, the volume matrix fractal dimension and the surface matrix fractal dimension, is a new index to characterize granules with irregular structures and evaluate the effects of production processes on the structures of granules as a new indicator for the granulating process control and optimization.

Assessment of quantitative structure-activity relationship of toxicity prediction models for Korean chemical substance control legislation

OBJECTIVES: For successful adoption of legislation controlling registration and assessment of chemical substances, it is important to obtain sufficient toxicological experimental evidence and other related information. It is also essential to obtain a sufficient number of predicted risk and toxicity results. Particularly, methods used in predicting toxicities of chemical substances during acquisition of required data, ultimately become an economic method for future dealings with new substances. Although the need for such methods is gradually increasing, the-required information about reliability and applicability range has not been systematically provided. METHODS: There are various representative environmental and human toxicity models based on quantitative structure-activity relationships (QSAR). Here, we secured the 10 representative QSAR-based prediction models and its information that can make predictions about substances that are expected to be regulated. We used models that predict and confirm usability of the information expected to be collected and submitted according to the legislation. After collecting and evaluating each predictive model and relevant data, we prepared methods quantifying the scientific validity and reliability, which are essential conditions for using predictive models. RESULTS: We calculated predicted values for the models. Furthermore, we deduced and compared adequacies of the models using the Alternative non-testing method assessed for Registration, Evaluation, Authorization, and Restriction of Chemicals Substances scoring system, and deduced the applicability domains for each model. Additionally, we calculated and compared inclusion rates of substances expected to be regulated, to confirm the applicability. CONCLUSIONS: We evaluated and compared the data, adequacy, and applicability of our selected QSAR-based toxicity prediction models, and included them in a database. Based on this data, we aimed to construct a system that can be used with predicted toxicity results. Furthermore, by presenting the suitability of individual predicted results, we aimed to provide a foundation that could be used in actual assessments and regulations.

Endoparasites of horses from the Formiga city, located in center-west region of the state of Minas Gerais, Brazil / Endoparasitas de equinos provenientes do município de Formiga, localizado na região Centro-oeste do estado de Minas Gerais, Brasil

With the aim of studying the endoparasite fauna of horses from the Formiga city, located in center-west region of the state of Minas Gerais, 25 animals that were naturally infected with helminths were evaluated. By means of parasitological necropsies, different endoparasites were found. The subfamily Cyathostominae presented the highest incidence, followed by Trichostrongylus axei, Oxyuris equi, Triodontophorus serratus, Strongyloides westeri, Strongylus edentatus, Habronema muscae, Parascaris equorum, Probstmayria vivipara, Strongylus vulgaris, Gasterophilus nasalis, Anoplocephala magna and Anoplocephala perfoliata. In the present study, if the species Probstmayria vivipara was not considered in the prevalence, the frequency of Cyathostominae was equivalent to 94.85%. The results obtained in this study allowed us to detect and identify different species of helminths in horses, and confirmed the high incidence of nematodes belonging to the subfamily Cyathostominae in the center-west region of Minas Gerais.

Com o objetivo de estudar a fauna de endoparasitas de equinos da Região Centro-Oeste do Estado de Minas Gerais, 25 animais naturalmente infectados por helmintos foram avaliados. Por meio de necropsias parasitológicas, diferentes endoparasitas foram identificados. A sub - família Cyathostominae apresentou maior incidência, seguido por Trichostrongylus axei, Oxyuris equi, Triodontophorus serratus, Strongyloides westeri, Strongylus edentatus, Habronema muscae, Parascaris equorum, Probstmayria vivipara, Strongylus vulgaris, Gasterophilus nasalis, Anoplocephala magna e Anoplocephala perfoliata. No presente estudo, se não for considerada a espécie Probstmayria vivipara na prevalência, a frequência de Cyathostominae é equivalente a 94,85%. Os resultados obtidos neste estudo, permitiu detectar e identificar diferentes espécies de helmintos em equinos, bem como confirmar a elevada incidência de nematódeos pertencentes à sub-família Cyathostominae na Região Centro-Oeste de Minas Gerais.

A comparative 2D QSAR study on a series of hydroxamic acid-based histone deacetylase inhibitors vis-à-vis comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA).

A quantitative structure-activity relationship (QSAR) study was performed on a series of indole amide analogues reported by Dai et al. [Bioorg Med Chem Lett (2003), 13, 1897-1901] to act as histone deacetylase (HDAC) inhibitors. The multiple regression analysis (MRA) revealed a model showing the significant dependence of the activity on molar refractivity (MR) and global topological charge index (GTCI) of the compounds, suggesting that inhibition of the HDAC by this series of compounds might involve the dispersion interaction with the receptor, where charge transfer between pairs of atoms might greatly help to polarize the molecule. The MRA results were then compared with those obtained by Guo et al. [Bioorg Med Chem (2005), 13, 5424-5434] by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). It was found that MRA gave as good results and had as good predictive ability as CoMFA and CoMSIA. Besides, MRA was also able to throw the light on the physicochemical properties of the molecules that were involved in drug-receptor interactions, while CoMFA and CoMSIA could not. The dispersion interaction between the molecule and the active site of the receptor is suggested to be the main interaction.

A quantitative structure-activity relationship (QSAR) study on a few series of potent, highly selective inhibitors of nitric oxide synthase.

QSAR study was performed on a series of 1,2-dihydro-4-quinazolinamines, 4,5-dialkylsubstituted-2-imino-1,3-thiazolidine derivatives and 4,5-disubstituted-1,3-oxazolidin-2-imine derivatives studied by Tinker et al. [J Med Chem (2003), 46, 913-916], Ueda et al. [Bioorg Med Chem (2004) 12, 4101-4116] and Ueda et al. [Bioorg Med Chem Lett (2004) 14, 313-316], respectively, as potent, highly selective inhibitors of inducible nitric oxide synthase (iNOS). The iNOS inhibition activity of the whole series of compounds was analyzed in relation to the physicochemical and molecular properties of the compounds. The QSAR analysis revealed that the inhibition potency of the compounds was controlled by a topological parameter 1v (Kier’s first order valence molecular connectivity index), density (D), surface tension (St) and length (steric parameter) of a substituent. This suggested that the drug-receptor interaction predominantly involved the dispersion interaction, but the bulky molecule would face steric problem because of which the molecule may not completely fit in active sites of the receptor and thus may not have the optimum interaction.

Pharmacophore mapping studies on pyrazoles as anti-proliferative agents

Pharmacophore mapping investigations were carried out on a dataset of 36 pyrazole derivatives that demonstrate antiproliferative activity in human ovarian adenocarcinoma A2780 cells. Pharmacophore modeling is a powerful tool for activity prediction of the ligands. Three point pharmacophore model was developed with two hydrophobic groups, one hydrogen bond acceptor, as pharmacophoric features. The pharmacophore hypothesis AHH.14 with R[2] value 0.909 yields a 3D-QSAR model which is statistically significant and best pharmacophore hypothesis. External validation of AHH.14 was performed by activity prediction of test set molecules with squared predictive correlation coefficient of 0.875 was observed between experimental and predicted activity values of test set molecules. AHH.14 pharmacophore model may offer potential for the design of antiproliferative agents via development of lead structures

Study on lipid-lowering traditional Chinese medicines based on pharmacophore technology and patent retrieval / 中国中药杂志

The combined application of statins that inhibit HMG-CoA reductase and fibrates that activate PPAR-α can produce a better lipid-lowering effect than the simple application, but with stronger adverse reactions at the same time. In the treatment of hyperlipidemia, the combined administration of TCMs and HMG-CoA reductase inhibitor in treating hyperlipidemia shows stable efficacy and less adverse reactions, and provides a new option for the combined application of drugs. In this article, the pharmacophore technology was used to search chemical components of TCMs, trace their source herbs, and determine the potential common TCMs that could activate PPAR-α. Because there is no hyperlipidemia-related medication reference in modern TCM classics, to ensure the high safety and efficacy of all selected TCMs, we selected TCMs that are proved to be combined with statins in the World Traditional/Natural Medicine Patent Database, analyzed corresponding drugs in pharmacophore results based on that, and finally obtained common TCMs that can be applied in PPAR-α and combined with statins. Specifically, the pharmacophore model was based on eight receptor-ligand complexes of PPAR-α. The Receptor-Ligand Pharmacophore Generation module in the DS program was used to build the model, optimize with the Screen Library module, and get the best sub-pharmacophore, which consisted of two hydrogen bond acceptor, three hydrophobic groups and 19 excluded volumes, with the identification effectiveness index value N of 2. 82 and the comprehensive evaluation index CAI value of 1. 84. The model was used to screen the TCMD database, hit 5,235 kinds of chemical components and 1 193 natural animals and plants, and finally determine 62 TCMs. Through patent retrieval, we found 38 TCMs; After comparing with the virtual screening results, we finally got seven TCMs.

Application of an R-group search strategy into three-dimensional quantitative structure-activity relationship of HEA beta-secretase inhibitors and molecular virtual screening / 生物医学工程学杂志

The beta-secretase is one of prospective targets against Alzheimer's disease (AD). A three-dimensional quan titative structure-activity relationship (3D-QSAR) model of Hydroethylamines (HEAs) as beta-secretase inhibitors was established using Topomer CoMFA. The multiple correlation coefficient of fitting, cross validation and external validation were r2 = 0.928, q(loo)2 = 0.605 and r(pred)2 = 0.626, respectively. The 3D-QSAR model was used to search R groups from ZINC database as the source of structural fragments. As a result, a series of R groups with relatively high activity contribution was obtained to design a total of 15 new compounds, with higher activity than that of the template molecule. The molecular docking was employed to study the interaction mode between the new compounds as ligands and beta-secretase as receptors, displaying that hydrogen bond and hydrophobicity played important roles in the binding affinity between the new compounds and beta-secretase. The results showed that Topomer CoMFA and To pomer Search could be effectively used to screen and design new molecules of HEAs as beta-secretase inhibitors, and the designed compounds could provide new candidates for drug design targeting AD.

Study on structure-activity relationship of flavonoids' multidrug resistance-associated protein inhibitory activity / 中国中药杂志

To study the quantitative structure-activity relationship (QSAR) between the stuctures of 29 flavonoids and the inhibitory activity of their multidrug resistance-associated protein (MRP) 1 and 2 by using the comparative molecular similarity index analysis (CoMSIA). By studying the impact of the combination of different molecular force fields, researchers obtained the molecular force fields that played an important role in inhibiting the activity of MRP1 and MRP2, built the optimized QSAR model, and discussed the structural modification method for flavonoids' multidrug resistance-associated protein inhibitor. The results of the study could not only provide the guidance for new drug R&D, but also help partially discuss the synergy mechanism between MRP1 and MRP2 receptors and traditional Chinese medicines containing flavonoids.