Quantitative Structure–Activity Relationship (QSAR) Studies of Some Glutamine Analogues for Possible Anticancer Activity

A Quantitative Structure–Activity Relationship (QSAR) study was performed to predict an anticancer activity in tumor cells of thirty-six 5-N-substituted-2-(substituted benzenesulphonyl) glutamines compounds using the electronic and topologic descriptors computed respectively, with ACD/ChemSketch and Gaussian 03W programs. The structures of all 36 compounds were optimized using the hybrid Density Functional Theory (DFT) at the B3LYP/6-31G(d) level of theory. In both approaches, 30 compounds were assigned as the training set and the rest as the test set. These compounds were analyzed by the Principal Components Analysis (PCA) method, a descendant Multiple Linear Regression (MLR), Multiple Nonlinear Regression (MNLR) analyses and an Artificial Neural Network (ANN). The robustness of the obtained models was assessed by leave-many-out cross-validation, and external validation through a test set.This study shows that the ANN has served marginally better to predict antitumor activity when compared with the results given by predictions made with MLR and MNL

In silico design of new α-glucosidase inhibitors through 3D-QSAR study, molecular docking modeling and ADMET analysis

α-Glucosidase enzyme is a therapeutic target for diabetes mellitus and its inhibitors shown a crucial importance in the treatment of this disease. Twenty oxindole based oxadiazole molecules were studied based on the combination between 3D-QSAR and molecular docking approaches in order to develop new α-glucosidase inhibitors with high predicted activities. The proposed CoMFA and CoMSIA models exhibited important Q2 values (0.544 and 0.605 respectively) and significant R2 values (0.977 and 0.935 respectively). The CoMFA and CoMSIA models were undergone to an external validation to test their proficiency; the produced R2test values are 0.950 and 0.804, respectively. Moreover, the contour maps produced by CoMFA and CoMSIA models have been exploited to determine the main groups influencing (decreasing or increasing) the α-glucosidase inhibitory activity. Therefore, two new oxindole based oxadiazole molecules with significant activities were proposed and designed. In a similar vein, molecular docking simulation was conducted to scrutinize the binding interactions between oxindole based oxadiazole molecules and α-glucosidase receptor (PDB code: 3A4A). Finally yet importantly, ADMET properties were predicted to assess the oral bioavailability of the proposed new compounds and examine their toxicity

New compounds based on 1H-pyrrolo[2,3-b] pyridine as potent TNIK inhibitors against colorectal cancer cells. Molecular modeling studies

Cancer is a disease caused by the incorrect transformation of cells that proliferate abnormally, and it is one of the leading causes of mortality worldwide. As a result, new compounds with potential anticancer activity must be designed. In this article, three – dimensional Quantitative Structure-Activity Relationship is used to study thirty-one compounds of 1H-pyrrolo[2,3-b]pyridine derivatives as potent TNIK inhibitors against colorectal cancer cells. Their pIC50 varied from 7.37 to 9.92. The two contours, Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices (CoMSIA) are critical in determining the nature of the groups that enhance or reduce activity. The models CoMFA and CoMSIA indicate strong reliability with (Q2 = 0.65; R2 = 0.86; rtest2 = 0.97) and (Q2= 0.74; R2 = 0. 96; rtest2 = 0. 95), respectively. Based on the good findings produced by the contour maps generated by the approach model, we have suggested five drugs with strong activity against colorectal cancer cells. In addition, the ADMET characteristics of these newly designed compounds were examined in silico. These compounds were further evaluated by molecular docking, showing that two molecules, Y4 and Y5, exhibit favorable interactions with the targeted receptor and a high total score. Our vision is to develop new medicines with strong TNIK inhibitory activities that target Traf2 and Nck-interacting kinase TNIK as a therapeutic target

In silico analysis of 3D QSAR and Molecular Docking studies to discover new thiadiazole-thiazolone derivatives as mitotic kinesin Eg5 inhibition

      A series of twenty one thiadiazole-thiazolone derivatives which is a class of highly potent human mitotic kinesin Eg5 inhibitor reported from published article were studied through a series of computer-aided drug design processes such as three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, including comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) and Surflex-docking method using 17 compounds as training set. Both models showed good statistical quality and satisfying predictive ability (Q2 = 0.617 and R2=0.919 for CoMFA ) and (Q2 = 0.638 and R2=0.919 for CoMSIA ). The aim of this study was to explore 3D-QSAR approaches to propose new thiadiazole-thiazolone derivatives as Eg5 inhibitors for human mitotic kinesin. The CoMFA/CoMSIA contour maps were generated to provide the information about regions where the activity might be increased or decreased.  Moreover, Based on the X-ray crystallized complex (PDB ID: 2UYM) molecular docking was performed on the most potent proposed Eg5 inhibitors using Surflex-dock method as an approach to investigate the stability of docked conformation and study the binding interactions in detail

Acute Upper Gastro-Intestinal Bleeding in Morocco: What Have Changed?

Objective. In the present study, we aimed to investigate epidemiological, clinical, and etiological characteristics of acute upper gastro-intestinal bleeding. Materials and Methods. This retrospective study was conducted between January 2003 and December 2008. It concerned all cases of acute upper gastroduodenal bleeding benefited from an urgent gastro-intestinal endoscopy in our department in Morocco. Characteristics of patients were evaluated in terms of age, gender, medical history, presenting symptoms, results of rectal and clinical examinations, and endoscopy findings. Results. 1389 cases were registered. As 66% of the patients were male, 34% were female. Mean age was 49. 12% of patients had a history of previous hemorrhage, and 26% had a history of NSAID and aspirin use. Endoscopy was performed in 96%. The gastroduodenal ulcer was the main etiology in 38%, followed by gastritis and duodenitis in 32.5%. Conclusion. AUGIB is still a frequent pathology, threatening patients' life. NSAID and aspirin are still the major risk factors. Their impact due to peptic ulcer remains stable in our country

Some new observations on the Volvariella genus Speg. 1898

Three fungal species of the Volvariella genus were described in this study. Volvariella bombycina and Volvaria speciosa were harvested at the level of the Mamora forest. V. media was collected from one garden grass in the city of Kenitra, this species is new to the Moroccan fungal flora

Non Hodgkin’s lymphoma secondary treatment with azathioprine in a chronic hepatitis autoimmune (second case of literature)

Les traitements immunosuppresseurs sont associés à une augmentation du risque de survenue de Lymphomes Malins Non Hodgkiniens (LMNH), en particulier chez les patients traités par azathioprine pour Maladies Inflammatoires Chroniques de l’Intestin (MICI), greffe d’organes, polyarthrite rhumatoïde. En revanche, nous ne disposons pas de données concernant la survenue LMNH sous azathioprine pour hépatite chronique auto-immune. Les auteurs rapportent le cas d’un patient traité par prednisolone et azathioprine, pendant 2 mois, suivis d’un relais par azathioprine seul en traitement d’entretien. L’évolution était favorable. Trois ans après, le patient a présenté un lymphome malin non hodgkinien ganglionnaire. À notre connaissance, cette observation illustre le deuxième cas de la littérature.Immunosuppressive treatments are associated with an increased risk of non-Hodgkin's lymphoma (LMNH), especially in patients treated with azathioprine for chronic inflammatory disease of the intestine (IBD), organ transplantation, rheumatoid arthritis. However, we do not have data on the occurrence LMNH under azathioprine for chronic hepatitis autoimmune. The authors report a case of patient receiving prednisolone and azathioprine for 2 months followed by a single relay azathioprine as maintenance treatment. The evolution was favourable. Three year later, the patient presented a malignant non-Hodgkin lymphoma ganglionnaire. In our knowledge, this observation is the second case reported in the literature

3D-QSAR, molecular docking, molecular dynamic simulation, and ADMET study of bioactive compounds against candida albicans

Candida albicans has developed significant levels of resistance to traditional antifungals, posing a danger to world health. In this research, the potential inhibitory of a class of twenty-five triazole molecules revealed an activity against candida albicans was addressed by using the three dimensional quantitative structure-activity relationship approach. The reliable models developed by CoMFA and CoMSIA/SEA exhibited high values of Q2 (0.620 and 0.733) respectively, and notable values of R2 (0.840 and 0.890) respectively. CoMFA and CoMSIA/SEA contour maps bring a set of information that may be invested to identify the key sites that have an important influence on the candida albicans activity. These findings lead us to design four new triazole compounds with good predicted activity. The new triazole molecules were undergone to in-depth study by assessing their oral bioavailability and toxicity using in silico ADMET prediction. The new molecules T1, T2 and T3 exhibited good properties in terms of numerous pharmacokinetics parameters as absorption, BBB penetration and toxicity. In addition, molecular docking was conducted to identify the types and mode of interactions between triazole ligands and the receptors. The reached findings appeared the high stability of the new triazole scaffolds at the active site of the receptor (PDB code: 2Y7L). The molecule T1 which is exhibited good stability in the active pocket of the receptor was further subjected to a molecular dynamics (MD) simulation using 20 ns in order to scrutinize the protein's comparative conformational dynamics following ligand binding. MD simulation for 20 ns reveals promising results for the molecule T1

Parking functions, labeled trees and DCJ sorting scenarios

In genome rearrangement theory, one of the elusive questions raised in recent years is the enumeration of rearrangement scenarios between two genomes. This problem is related to the uniform generation of rearrangement scenarios, and the derivation of tests of statistical significance of the properties of these scenarios. Here we give an exact formula for the number of double-cut-and-join (DCJ) rearrangement scenarios of co-tailed genomes. We also construct effective bijections between the set of scenarios that sort a cycle and well studied combinatorial objects such as parking functions and labeled trees.Comment: 12 pages, 3 figure