New Issue | Current Computer-Aided Drug Design; Volume 16 Issue 2

 

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Current Computer-Aided Drug Design aims to publish all the latest developments in drug design based on computational techniques. The field of computer-aided drug design has had extensive impact in the area of drug design.

Current Computer-Aided Drug Design is an essential journal for all medicinal chemists who wish to be kept informed and up-to-date with all the latest and important developments in computer-aided methodologies and their applications in drug discovery. Each issue contains a series of timely, in-depth reviews/mini-reviews, original research articles and letter articles written by leaders in the field, covering a range of computational techniques for drug design, screening, ADME studies, theoretical chemistry; computational chemistry; computer and molecular graphics; molecular modeling; protein engineering; drug design; expert systems; general structure-property relationships; molecular dynamics; chemical database development and usage etc., providing excellent rationales for drug development.

 

Articles from the journal: Current Computer-Aided Drug Design; Volume 16 Issue 2:

 

For details on the articles, please visit this link: http://www.eurekaselect.com/node/582/current-computer-aided-drug-design/issue/16/2727/2/9757

Aims & Scope | Current Computer-Aided Drug Design

 

AIMS & SCOPE

Current Computer-Aided Drug Design aims to publish all the latest developments in drug design based on computational techniques. The field of computer-aided drug design has had extensive impact in the area of drug design.

Current Computer-Aided Drug Design is an essential journal for all medicinal chemists who wish to be kept informed and up-to-date with all the latest and important developments in computer-aided methodologies and their applications in drug discovery. Each issue contains a series of timely, in-depth reviews/mini-reviews, original research articles and letter articles written by leaders in the field, covering a range of computational techniques for drug design, screening, ADME studies, theoretical chemistry; computational chemistry; computer and molecular graphics; molecular modeling; protein engineering; drug design; expert systems; general structure-property relationships; molecular dynamics; chemical database development and usage etc., providing excellent rationales for drug development.

 

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Most Accessed Articles | Graphitization Behavior of Single Crystal Diamond for the Application in Nano-Metric Cutting

Journal Name: Current Nanoscience

Author(s): Qingshun Bai*, Zhiguo Wang, Yongbo Guo, Jiaxuan Chen, Yuanjiang Shang.

Graphical Abstract:

Abstract:

Background: Graphitization behavior of diamond has received an increasing interest in nanoscale machining of some hard and brittle materials. Diamond has always been an important and excellent tool material in cutting area. However, the graphitization of the diamond tool is inevitable when it was used in special conditions. It is indicated that the graphitization of diamond crystal has great influence on the wear resistance of diamond cutting tool. The graphitization behavior needs to be investigated extensively in nanoscale with an atomic view. Molecular dynamics simulation provides a useful tool for understanding of the graphitization mechanism of diamond. The investigation on graphitization behavior of single crystal diamond can also provide a useful reference for the application of diamond cutting tool.

Materials and Methods: In this paper, a molecular dynamics (MD) diamond crystal model is built to examine the graphitization behavior of diamond under various conditions. The sixfold ring method was employed to identify the structural characteristics of graphite and diamond. The effects of temperature and crystal orientation on the graphitization of diamond have been revealed. Considering the effect of temperature, the anisotropy of diamond graphitization against various crystal planes is presented and discussed carefully. The nano-metric cutting model of diamond tool evaluated by the sixfold ring method also proves the graphitization mechanisms in atomic view.

Results: Results indicate that the sixfold ring method is a reliable method to evaluate the graphitization behavior of diamond crystal. There exists a critical temperature of the graphitization of diamond. The results also show that {111} plane is more easy to get graphitization as compared with other crystal planes. However, {100} plane of diamond model presents the highest antigraphitization property.

Conclusion: The obtained results have provided the in-depth understanding on the wear of diamond tool in nano-metric machining and underpin the development of diamond cutting tool.

 

Read out more at: http://www.eurekaselect.com/162223

ARTICLE BY DISEASE – Docking and Molecular Dynamics Study on the Inhibitory Activity of Novel Inhibitors on Epidermal Growth Factor Receptor (EGFR)

ARTICLE BY DISEASE ON ” ANAL CANCER “

 

 

Abstract:

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.

 

For more details, please visit: http://www.eurekaselect.com/node/87265/article

EDITORS CHOICE ARTICLE – Dimerization of C-terminal Truncations of α-synuclein and its Effect on the Aggregation Propensity: A Potential of Mean Force Study

Journal Name: Current Chemical Biology

Author(s): Airy Sanjeev, Venkata Satish Kumar Mattaparthi*.

 

 

 

 

 

Graphical Abstract:

 

Abstract:

Background: The occurrence of Parkinson’s Disease (PD) is associated with the deposition of proteinaceous aggregates formed by the self-assembly of α-synuclein protein. The pathogenesis of PD has been reported to be linked with the α-synuclein gene. However, the presence of missense mutations: A30P, A53T, E46K, H50Q, G51D and A53E has also been linked with the autosomal inheritance of PD. Recently, it has been highlighted that C-terminal truncated α-synucleins undergo aggregation at a faster rate while the full-length α-synucleins are critical.

Objective: To study the dimerization of C-terminal truncations of α-synuclein and its effect on the aggregation propensity.

Methodology: We investigated the dimerization of the two important C-terminal truncations (120 and 123) of α-synuclein using Molecular Dynamics Simulation and Potential of Mean Force (PMF) study.

Results: From our PMF study, we observed that the binding free energy value to be larger for the association of C-terminal truncated α-synucleins than the value that has been reported for Wild-Type (WT) in our earlier study.

Conclusion: Truncating the C-terminal region (which is considered to be intra-molecular chaperone) in α-synucleins exposes the hydrophobic region and thereby increases the aggregation propensity.

READ MORE HERE: http://www.eurekaselect.com/161697/article 

EDITOR’S CHOICE – Inhibitory Effects of 1,4-disubstituted Thiosemicarbazide Derivatives on Streptococcus mutans and Streptococcus sanguinis Mono-species Biofilms

Journal: Letters in Drug Design & Discovery

Author(s): Malgorzata Miazga-Karska, Maciej Wos, Agnieszka A. Kaczor, Anna Pachuta-Stec, Grazyna Ginalska, Monika Pitucha*

Graphical Abstract:

 

Abstract:

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. 3.0.3.1.4.

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

 

 

MOST ACCESSED ARTICLE – Decoding Corticotropin-Releasing Factor Receptor Type 1 Crystal Structures – Current Molecular Pharmacology

Journal: Current Molecular Pharmacology

Author(s): Andrew S. Dore, Andrea Bortolato, Kaspar Hollenstein, Robert K.Y. Cheng, Randy J. Read, Fiona H. Marshall

Graphical Abstract:

 

Abstract:

The structural analysis of class B G protein-coupled receptors (GPCR), cell surface proteins responding to peptide hormones, has until recently been restricted to the extracellular domain (ECD). Corticotropin-releasing factor receptor type 1 (CRF1R) is a class B receptor mediating stress response and also considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of human CRF1R in complex with the small-molecule antagonist CP-376395 in a hexagonal setting with translational non-crystallographic symmetry. Molecular dynamics and metadynamics simulations on this novel structure and the existing TMD structure for CRF1R provides insight as to how the small molecule ligand gains access to the induced-fit allosteric binding site with implications for the observed selectivity against CRF2R. Furthermore, molecular dynamics simulations performed using a full-length receptor model point to key interactions between the ECD and extracellular loop 3 of the TMD providing insight into the full inactive state of multidomain class B GPCRs.

To access the article, please visit: http://www.eurekaselect.com/149116

 

Open Access Article – Decoding Corticotropin-Releasing Factor Receptor Type 1 Crystal Structures – Current Molecular Pharmacology

Journal:  Current Molecular Pharmacology

Author(s): Andrew S. Dore, Andrea Bortolato, Kaspar Hollenstein, Robert K.Y. Cheng, Randy J. Read, Fiona H. Marshall.

Graphical Abstract:

 

Abstract:

The structural analysis of class B G protein-coupled receptors (GPCR), cell surface proteins responding to peptide hormones, has until recently been restricted to the extracellular domain (ECD). Corticotropin-releasing factor receptor type 1 (CRF1R) is a class B receptor mediating stress response and also considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of human CRF1R in complex with the small-molecule antagonist CP-376395 in a hexagonal setting with translational non-crystallographic symmetry. Molecular dynamics and metadynamics simulations on this novel structure and the existing TMD structure for CRF1R provides insight as to how the small molecule ligand gains access to the induced-fit allosteric binding site with implications for the observed selectivity against CRF2R. Furthermore, molecular dynamics simulations performed using a full-length receptor model point to key interactions between the ECD and extracellular loop 3 of the TMD providing insight into the full inactive state of multidomain class B GPCRs.

Read more here: http://www.eurekaselect.com/149116/article

 

 

Testimonial by Indu Kumari!

Indu Kumari

Contributed Article: “Molecular Dynamics Simulations, Challenges and Opportunities: A Biologist’s Prospective

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