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Journal Name: Current Enzyme Inhibition
Background: Protein tyrosine phosphatase non-receptor type 1 is a therapeutic target for the type 2 diabetes mellitus. According to the International Diabetes Federation 2015 report, one out of 11 adults suffers from diabetes mellitus globally.
Objective: Current anti-diabetic drugs can cause life-threatening side-effects. The present study proposes a pipeline for the development of effective and plant-derived anti-diabetic drugs that may be safer and better tolerated.
Methods: Plant-derived protein tyrosine phosphatase non-receptor type 1 inhibitors possessing antidiabetic activity less than 10µM were used as a training set. A common feature pharmacophore model was generated. Pharmacophore-based screening of plant-derived compounds of the ZINC database was conducted using ZINCpharmer. Screened hits were assessed to evaluate their drug-likeness, pharmacokinetics, detailed binding behavior, and aggregator possibility based on their physiochemical properties and chemical similarity with reported aggregators.
Results: Through virtual screening and in silico pharmacology protocol isosilybin (ZINC30731533) was identified as a lead compound with optimal properties. This compound can be recommended for laboratory tests and further analyses to confirm its activity as protein tyrosine phosphatase nonreceptor type 1 inhibitor.
Conclusion: The present study has identified plant-derived anti-diabetic virtual lead compound with the potential to inhibit protein tyrosine phosphatase non-receptor type 1, which may be helpful to enhance insulin production. This computer-aided study could facilitate the development of novel pharmacological inhibitors for diabetes treatment. To read out more, please visit: http://www.eurekaselect.com/151386/article
Author(s): Suraj N. Mali*, Sudhir Sawant, Hemchandra K. Chaudhari*, Mustapha C. Mandewale
Background: Thiadiazole not only acts as “hydrogen binding domain” and “two-electron donor system” but also as constrained pharmacophore.
Methods: The maleate salt of 2-((2-hydroxy-3-((4-morpholino-1, 2,5-thiadiazol-3-yl) oxy) propyl) amino)- 2-methylpropan-1-ol (TML-Hydroxy)(4) has been synthesized. This methodology involves preparation of 4-morpholino-1, 2,5-thiadiazol-3-ol by hydroxylation of 4-(4-chloro-1, 2,5-thiadiazol-3-yl) morpholine followed by condensation with 2-(chloromethyl) oxirane to afford 4-(4-(oxiran-2-ylmethoxy)-1,2,5-thiadiazol- 3-yl) morpholine. Oxirane ring of this compound was opened by treating with 2-amino-2-methyl propan-1- ol to afford the target compound TML-Hydroxy. Structures of the synthesized compounds have been elucidated by NMR, MASS, FTIR spectroscopy.
Results: The DSC study clearly showed that the compound 4-maleate salt is crystalline in nature. In vitro antibacterial inhibition and little potential for DNA cleavage of the compound 4 were explored. We extended our study to explore the inhibition mechanism by conducting molecular docking, ADMET and molecular dynamics analysis by using Schrödinger. The molecular docking for compound 4 showed better interactions with target 3IVX with docking score of -8.508 kcal/mol with respect to standard ciprofloxacin (docking score= -3.879 kcal/mol). TML-Hydroxy was obtained in silico as non-carcinogenic and non-AMES toxic with good percent human oral absorption profile (69.639%). TML-Hydroxy showed the moderate inhibition against Mycobacteria tuberculosis with MIC 25.00 μg/mL as well as moderate inhibition against S. aureus, Bacillus sps, K. Pneumoniae and E. coli species.
Conclusion: In view of the importance of the 1,2,5-thiadiazole moiety involved, this study would pave the way for future development of more effective analogs for applications in medicinal field. For article details, please visit: http://www.eurekaselect.com/169670/article
Background: Human immunodeficiency virus (HIV) is an infective agent that causes an acquired immunodeficiency syndrome (AIDS). Therefore, the rational design of inhibitors for preventing the progression of the disease is required.
Objective: This study aims to construct quantitative structure-activity relationship (QSAR) models, molecular docking and newly rational design of colchicine and derivatives with anti-HIV activity.
Methods: A data set of 24 colchicine and derivatives with anti-HIV activity were employed to develop the QSAR models using machine learning methods (e.g. multiple linear regression (MLR), artificial neural network (ANN) and support vector machine (SVM)), and to study a molecular docking.
Results: The significant descriptors relating to the anti-HIV activity included JGI2, Mor24u, Gm and R8p+ descriptors. The predictive performance of the models gave acceptable statistical qualities as observed by correlation coefficient (Q2) and root mean square error (RMSE) of leave-one out cross-validation (LOO-CV) and external sets. Particularly, the ANN method outperformed MLR and SVM methods that displayed LOO−CV 2 Q and RMSELOO-CV of 0.7548 and 0.5735 for LOOCV set, and Ext 2 Q of 0.8553 and RMSEExt of 0.6999 for external validation. In addition, the molecular docking of virus-entry molecule (gp120 envelope glycoprotein) revealed the key interacting residues of the protein (cellular receptor, CD4) and the site-moiety preferences of colchicine derivatives as HIV entry inhibitors for binding to HIV structure. Furthermore, newly rational design of colchicine derivatives using informative QSAR and molecular docking was proposed.
Conclusion: These findings serve as a guideline for the rational drug design as well as potential development of novel anti-HIV agents. To read out more, please visit: http://www.eurekaselect.com/165617/article
Currently, new chemical entities developed as anticancer agents against tubulin as a protein target. The present work, a quinazoline derivatives were used to design and synthesized by microwave irradiation as an anticancer agent through selective inhibitors of colchicinebinding site of tubulin by the molecular docking of quinazoline derivatives using Schrödinger, LLC, New York, NY, 2017. Read out full article here: http://www.eurekaselect.com/166586/article
EGFR is the cell-surface receptor. Its overexpression or overactivity has been associated with a number of cancers, including breast, lung, ovarian, and anal cancers. Many therapeutic approaches are aimed at the EGFR. A series of 2, 7-diamino-thiazolo [4,5-d] pyrimidine analogues are among the most highly potent and selective inhibitors of EGFR described to date. For in-depth investigation into the structural and chemical features responsible for the binding recognition mechanism concerned, as well as for exploring the binding pocket of these compounds, we performed a series of automated molecular docking operations. It was revealed that the binding site consisted of three main areas (P1, P2 and P3) composed of most of the hydrophobic amino acids able to accommodate the lipophilic arms of the compounds investigated. However, the solvent interface did not make much contribution to the binding of the inhibitors. The presence of residues Met793 and Asp855 may also be responsible for the binding recognition through H-bond interactions, with Phe856 through a T-shape π-π stacking interaction. The interaction model and pharmacophore of EGFR inhibitors were derived that can be successfully used to explain the different biologic activities of these inhibitors. Moreover, the docking results were quite robust as further validated by molecular dynamics. It is anticipated that the findings reported here may provide very useful information or clue for designing effective drugs for the therapeutic treatment of EGFR-related cancer.
Molecular docking, as one of the widely used virtual screening methods, aims to predict the binding-conformations of small molecule ligands to the appropriate target binding site. Because of the computational complexity and the arrival of the big data era, molecular docking requests High- Performance Computing (HPC) to improve its performance and accuracy. We discuss, in detail, the advances in accelerating molecular docking software in parallel, based on the different common HPC platforms, respectively. Not only the existing suitable programs have been optimized and ported to HPC platforms, but also many novel parallel algorithms have been designed and implemented. This review focuses on the techniques and methods adopted in paralyzing docking software. Where appropriate, we refer readers to exemplary case studies.
Background: Breast cancer is the most common invasive cancer in female worldwide. Indole scaffold represents an important class of therapeutic agents in medicinal chemistry. Many indole derivatives are reported as potent anticancer agents. This study aims to design, and synthesize anti-breast cancer potential of new bisindole derivatives.
Method: The target molecules were prepared by reacting cyano acetyl indoles with substituted indole-3- carboxyaldehydes in the presence of piperidine. All the newly synthesized compounds were in vitro screened for their anticancer activities against breast carcinoma (MCF-7) by employing the sulforhodamine B (SRB) assay method.
Results: Preliminary in vitro evaluation indicated that most of the compounds possess distinct cytotoxicity profile against MCF-7 cell line compared to standard drug adriamycin. Among them, compounds 5g, 5b, and 5q demonstrated excellent activities against breast carcinoma (GI50 < 0.1µM) as good as adriamycin (GI50 < 0.1µM). Active compounds were further subjected for molecular docking and bioavailability studies. These studies supported activities of the present series compounds.
Conclusion: New anti-breast cancer agents are the need of time, we believe that the new α-cyano substituted 1,3-bisindolyl-2-propen-1-one derivative 5g reported in this work may provide an interesting insight for further optimization.
Read more here: http://www.eurekaselect.com/151992/article
Journal: Letters in Drug Design & Discovery
Background: Bacterial biofilms are a cause of a number of infections and are associated with specific drug resistance. In particular, dental biofilm can consist of up to 100 bacterial species and may result in the diseases in the teeth and the surrounding tissues, including dental caries and periodontal diseases. Moreover, pathogens from the dental biofilm can migrate to other organs and lead to systemic diseases. Thus, it is important to search for inhibitors of dental biofilm formation. The series of 1,4-disubstitued thiosemicarbazide derivatives were evaluated for their ability to inhibit mono-species Streptococcus mutans or Streptococcus sanguinis biofilm formation.
Methods: The Minimum Biofilm Inhibitory Concentration (MBIC) is defined as the lowest concentration of an antimicrobial agent required to inhibit the formation of biofilm. MBIC was determined spectrophotometrically. Molecular docking was performed using Glide from the Schrödinger suite of software. The grid file was generated indicating acarbose as a reference ligand. The compounds were modeled using LigPrep protocol from the Schrödinger suite of software. Molecular docking was performed using the SP (standard precision) protocol of Glide. Molecular dynamics studies of ligand-receptor complexes was performed using Desmond v. 184.108.40.206.4.
Results: The series of 1,4-disubstituted thiosemicarbazide derivatives were synthesized and investigated for their ability to inhibit S. mutans or S. sanguinis biofilm. The most active compounds caused inhibition of S. sanguinis and S. mutans biofilm formation in the concentration of 7.81 µg/ml- 62.5 µg/ml. We showed, that growth of S. mutans and S. sanguinis biofilm was faster and higher in presence of sucrose. Additionally it was harder to inhibit the growth of biofilm in BHIbroth with the presence of sucrose, than the biofilm growing in BHI without sucrose. It seems that colonization by tested caries bacteria depends on sucrose content in medium. Based on above in vitro anti-biofilm data, we postulated that the mechanism of antibacterial activity of the investigated compounds might be connected with the inhibition of mono-species bacteria biofilm formation. In order to demonstrate that the investigated compounds may inhibit the enzyme glucansucrase and thus, biofilm formation, we performed molecular docking and molecular dynamics of the studied compounds to glucansucrase crystal structure. The obtained results reveal that the thiosemicarbazide derivatives can be used as potential inhibitors of dental biofilm formation, acting possibly through inhibition of glucansucrase.
Conclusion: In this study we showed that some of tested thiosemicarbazide derivatives can be used as potential inhibitors for mono-species cultures of S. mutans or S. sanguinis biofilm. The possible blocking mechanism of mono-species biofilm formation was proposed via molecular modelling technique. The data suggested that this mechanism may involve the glucansucrase inhibition as it was demonstrated that tested derivatives occupy the same binding pocket in this enzyme as acarbose, commonly known inhibitor of glucosylotransferases. Therefore, it is possible that tested derivatives could be used in prevention of dental caries.
Read more here: http://www.eurekaselect.com/156376/article
Journal: Letters in Drug Design & Discovery
Background: Alzheimer’s Disease (AD) is a complicated neurodegenerative disorder with a multifaceted pathogenesis.AD, characterized by gradual memory loss, falling in language ability and other cognitive deterioration, and has been a prominent risk to ageing population. This means that there is an urgent need to find new lead compounds for controlling and fighting against (AD). In this way, a new thiophene-2-pyrazoline derivatives (A1-A5) and benzothiazole derivatives (A6-A13) have been synthesized to give beneficial compounds to controlling and battling against (AD).
Results: Compounds A5 and A13 showed the most remarkable activity with an 18.53 µM and 15.26 µM IC50 values against AChE enzyme. In like manner, compound A4 was active with a 20.34 µM IC50 value against MAO-A. These active compounds are in fact non-toxic making them very attractive for additional future studies. Enzyme kinetic was analyzed and the Lineweaver-Burk plot reveals that compound A13 was typically mixed AChE inhibitors, which showed significant similarity to donepezil. In addition, the best docking pose was done by analyzing the docking pattern of the most active compound A13 which was very compatible with the gorge and in interaction with both CAS and PAS.
Conclusion: The synthesis of new thiophene-2-pyrazoline and benzothiazole derivatives targeting AChE/(MAO-A)/(MAO-B) enzymes was described. The selection of enzyme-kinetic analysis, molecular docking and toxicity test was led to good understanding to the therapeutic potential for the active derivatives. Therefore, these compounds may be accepted as promising leads for future research efforts in fighting against AD.
Read more here: http://www.eurekaselect.com/153764/article