scholarly journals Identification of non-classical hCA XII inhibitors using combination of computational approaches for drug design and discovery

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mohammad M. Al-Sanea ◽  
Garri Chilingaryan ◽  
Narek Abelyan ◽  
Grigor Arakelov ◽  
Harutyun Sahakyan ◽  
...  
Keyword(s):  
Drug Design ◽  
Cancer Cell Proliferation ◽  
Computational Approaches ◽  
Therapeutic Value ◽  
Different Types ◽  
The Subject ◽  
Pharmacological Target ◽  
Dynamics Simulations ◽  
Pharmacophore Models ◽  
Sulfonamide Group

AbstractHuman carbonic anhydrase XII (hCA XII) isozyme is of high therapeutic value as a pharmacological target and biomarker for different types of cancer. The hCA XII is one of the crucial effectors that regulates extracellular and intracellular pH and affects cancer cell proliferation, invasion, growth and metastasis. Despite the fact that interaction features of hCAs inhibitors with the catalytic site of the enzyme are well described, lack in the selectivity of the traditional hCA inhibitors based on the sulfonamide group or related motifs is an urgent issue. Moreover, drugs containing sulfanomides can cause sulfa allergies. Thus, identification of novel non-classical inhibitors of hCA XII is of high priority and is currently the subject of a vast field of study. This study was devoted to the identification of novel potential hCA XII inhibitors using comprehensive set of computational approaches for drug design discovery: generation and validation of structure- and ligand-based pharmacophore models, molecular docking, re-scoring of virtual screening results with MMGBSA, molecular dynamics simulations, etc. As the results of the study several compounds with alternative to classical inhibitors chemical scaffolds, in particular one of coumarins derivative, have been identified and are of high interest as potential non-classical hCA XII inhibitors.

scholarly journals Virtual screening of the potential hCA XII inhibitors based on the pharmacophore modelling, molecular docking, MMGBSA and molecular dynamics simulations studies

2021 ◽  
Author(s):  
Mohammad M. Al-Sanea ◽  
Garri Chilingaryan ◽  
Narek Abelyan ◽  
Grigor Arakelov ◽  
Harutyun Sahakyan ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Pharmacophore Modelling ◽  
Therapeutic Value ◽  
Different Types ◽  
Pharmacological Target ◽  
Dynamics Simulations ◽  
Derivatives Of ◽  
Pharmacophore Models

Abstract Human carbonic anhydrase XII (hCA XII) has gained therapeutic value in the field of medicinal chemistry as a pharmacological target and biomarker for different types of cancer. Despite the fact that interaction features of hCAs inhibitors with the catalytic site of the enzyme are well described, lack in the selectivity of the traditional hCA inhibitors is an urgent issue. This study was devoted to the identification of novel potential hCA XII inhibitors using comprehensive set of computational approaches, including generation of structure-and ligand-based pharmacophore models, molecular docking, MMGBSA calculations and molecular dynamics simulations. As the results of the study multiple potential hCA inhibitors were identified. Along with the identified derivatives of the classical hCA inhibitors (have sulfonamide motifs), several compounds with alternative chemical scaffolds, that can be considered and further investigated as potential non-classical hCA XII inhibitors, were identified.

Point and planar defects in the iron sulfide compounds Fe1-xS

1984 ◽  
Vol 42 ◽  
pp. 434-435
Author(s):  
Thao A. Nguyen
Keyword(s):  
Low Temperatures ◽  
Direct Evidence ◽  
Iron Sulfide ◽  
Planar Defects ◽  
Selective Area ◽  
Vacancy Ordering ◽  
Different Types ◽  
Lattice Images ◽  
The Subject ◽  
Beam Lattice

It is well known that the large deviations from stoichiometry in iron sulfide compounds, Fe1-xS (0≤x≤0.125), are accommodated by iron vacancies which order and form superstructures at low temperatures. Although the ordering of the iron vacancies has been well established, the modes of vacancy ordering, hence superstructures, as a function of composition and temperature are still the subject of much controversy. This investigation gives direct evidence from many-beam lattice images of Fe1-xS that the 4C superstructure transforms into the 3C superstructure (Fig. 1) rather than the MC phase as previously suggested. Also observed are an intrinsic stacking fault in the sulfur sublattice and two different types of vacancy-ordering antiphase boundaries. Evidence from selective area optical diffractograms suggests that these planar defects complicate the diffraction pattern greatly.

Experimental and Computational Approaches to Improve Binding Affinity in Chemical Biology and Drug Discovery

2020 ◽  
Vol 20 (19) ◽  
pp. 1651-1660
Author(s):  
Anuraj Nayarisseri
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Binding Affinity ◽  
Chemical Biology ◽  
De Novo ◽  
Structure Based Drug Design ◽  
Computational Approaches ◽  
Drug Designing ◽  
Traditional Drug ◽  
Computer Based

Drug discovery is one of the most complicated processes and establishment of a single drug may require multidisciplinary attempts to design efficient and commercially viable drugs. The main purpose of drug design is to identify a chemical compound or inhibitor that can bind to an active site of a specific cavity on a target protein. The traditional drug design methods involved various experimental based approaches including random screening of chemicals found in nature or can be synthesized directly in chemical laboratories. Except for the long cycle design and time, high cost is also the major issue of concern. Modernized computer-based algorithm including structure-based drug design has accelerated the drug design and discovery process adequately. Surprisingly from the past decade remarkable progress has been made concerned with all area of drug design and discovery. CADD (Computer Aided Drug Designing) based tools shorten the conventional cycle size and also generate chemically more stable and worthy compounds and hence reduce the drug discovery cost. This special edition of editorial comprises the combination of seven research and review articles set emphasis especially on the computational approaches along with the experimental approaches using a chemical synthesizing for the binding affinity in chemical biology and discovery as a salient used in de-novo drug designing. This set of articles exfoliates the role that systems biology and the evaluation of ligand affinity in drug design and discovery for the future.

Geological Field Sketches and Illustrations

2019 ◽  
Author(s):  
Matthew J. Genge
Keyword(s):  
Cross Sections ◽  
Earth Science ◽  
Three Dimensional ◽  
Worked Examples ◽  
Scientific Publications ◽  
Thin Sections ◽  
Geological Features ◽  
Different Types ◽  
The Subject

Drawings, illustrations, and field sketches play an important role in Earth Science since they are used to record field observations, develop interpretations, and communicate results in reports and scientific publications. Drawing geology in the field furthermore facilitates observation and maximizes the value of fieldwork. Every geologist, whether a student, academic, professional, or amateur enthusiast, will benefit from the ability to draw geological features accurately. This book describes how and what to draw in geology. Essential drawing techniques, together with practical advice in creating high quality diagrams, are described the opening chapters. How to draw different types of geology, including faults, folds, metamorphic rocks, sedimentary rocks, igneous rocks, and fossils, are the subjects of separate chapters, and include descriptions of what are the important features to draw and describe. Different types of sketch, such as drawings of three-dimensional outcrops, landscapes, thin-sections, and hand-specimens of rocks, crystals, and minerals, are discussed. The methods used to create technical diagrams such as geological maps and cross-sections are also covered. Finally, modern techniques in the acquisition and recording of field data, including photogrammetry and aerial surveys, and digital methods of illustration, are the subject of the final chapter of the book. Throughout, worked examples of field sketches and illustrations are provided as well as descriptions of the common mistakes to be avoided.

scholarly journals The Crosstalk Between Long Non-Coding RNAs and Various Types of Death in Cancer Cells

2021 ◽  
Vol 20 ◽  
pp. 153303382110330
Author(s):  
Wenwen Tang ◽  
Shaomi Zhu ◽  
Xin Liang ◽  
Chi Liu ◽  
Linjiang Song
Keyword(s):  
Cell Death ◽  
Cancer Cell ◽  
Causes Of Death ◽  
Vital Role ◽  
Cancer Cell Proliferation ◽  
Biological Targets ◽  
Cancer Cell Death ◽  
Different Types ◽  
Non Coding Rnas ◽  
Tumor Death

With the increasing aging population, cancer has become one of the leading causes of death worldwide, and the number of cancer cases and deaths is only anticipated to grow further. Long non-coding RNAs (lncRNAs), which are closely associated with the expression level of downstream genes and various types of bioactivity, are regarded as one of the key regulators of cancer cell proliferation and death. Cell death, including apoptosis, necrosis, autophagy, pyroptosis, and ferroptosis, plays a vital role in the progression of cancer. A better understanding of the regulatory relationships between lncRNAs and these various types of cancer cell death is therefore urgently required. The occurrence and development of tumors can be controlled by increasing or decreasing the expression of lncRNAs, a method which confers broad prospects for cancer treatment. Therefore, it is urgent for us to understand the influence of lncRNAs on the development of different modes of tumor death, and to evaluate whether lncRNAs have the potential to be used as biological targets for inducing cell death and predicting prognosis and recurrence of chemotherapy. The purpose of this review is to provide an overview of the various forms of cancer cell death, including apoptosis, necrosis, autophagy, pyroptosis, and ferroptosis, and to describe the mechanisms of different types of cancer cell death that are regulated by lncRNAs in order to explore potential targets for cancer therapy.

scholarly journals A QM/MM Evaluation of the Missing Step in the Reduction Mechanism of HMG-CoA by Human HMG-CoA Reductase

Processes ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 1085
Author(s):  
Paula Mihaljević-Jurič ◽  
Sérgio F. Sousa
Keyword(s):  
Mevalonate Pathway ◽  
Atomic Level ◽  
Amino Acid Residues ◽  
Protonation State ◽  
Primary Target ◽  
Cholesterol Levels ◽  
The Subject ◽  
Electron Reduction ◽  
Dynamics Simulations ◽  
Coa Reductase

Statins are important drugs in the regulation of cholesterol levels in the human body that have as a primary target the enzyme β-hydroxy-β-methylglutaryl-CoA reductase (HMGR). This enzyme plays a crucial role in the mevalonate pathway, catalyzing the four-electron reduction of HMG-CoA to mevalonate. A second reduction step of this reaction mechanism has been the subject of much speculation in the literature, with different conflicting theories persisting to the present day. In this study, the different mechanistic hypotheses were evaluated with atomic-level detail through a combination of molecular dynamics simulations (MD) and quantum mechanics/molecular mechanics (QM/MM) calculations. The obtained Gibbs free activation and Gibbs free reaction energy (15 kcal mol−1 and −40 kcal mol−1) show that this hydride step takes place with the involvement of a cationic His405 and Lys639, and a neutral Glu98, while Asp715 remains in an anionic state. The results provide an atomic-level portrait of this step, clearly demonstrating the nature and protonation state of the amino acid residues involved, the energetics associated, and the structure and charge of the key participating atoms in the several intermediate states, finally elucidating this missing step.

scholarly journals A Comprehensive Review of Cholinesterase Modeling and Simulation

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 580
Author(s):  
Danna De Boer ◽  
Nguyet Nguyen ◽  
Jia Mao ◽  
Jessica Moore ◽  
Eric J. Sorin
Keyword(s):  
Modeling And Simulation ◽  
Binding Site ◽  
Catalytic Efficiency ◽  
Site Location ◽  
Simulation Techniques ◽  
Therapeutic Value ◽  
Docking Calculations ◽  
Computer Based ◽  
Dynamics Simulations ◽  
And Function

The present article reviews published efforts to study acetylcholinesterase and butyrylcholinesterase structure and function using computer-based modeling and simulation techniques. Structures and models of both enzymes from various organisms, including rays, mice, and humans, are discussed to highlight key structural similarities in the active site gorges of the two enzymes, such as flexibility, binding site location, and function, as well as differences, such as gorge volume and binding site residue composition. Catalytic studies are also described, with an emphasis on the mechanism of acetylcholine hydrolysis by each enzyme and novel mutants that increase catalytic efficiency. The inhibitory activities of myriad compounds have been computationally assessed, primarily through Monte Carlo-based docking calculations and molecular dynamics simulations. Pharmaceutical compounds examined herein include FDA-approved therapeutics and their derivatives, as well as several other prescription drug derivatives. Cholinesterase interactions with both narcotics and organophosphate compounds are discussed, with the latter focusing primarily on molecular recognition studies of potential therapeutic value and on improving our understanding of the reactivation of cholinesterases that are bound to toxins. This review also explores the inhibitory properties of several other organic and biological moieties, as well as advancements in virtual screening methodologies with respect to these enzymes.

scholarly journals On Understanding the Administrative Law Subject

2020 ◽  
Vol 12 ◽  
pp. 18-20
Author(s):  
Olga N. Ordina ◽  
Keyword(s):  
Public Administration ◽  
Legal Theory ◽  
Administrative Law ◽  
Executive Power ◽  
Legal Science ◽  
Different Types ◽  
Common Concept ◽  
The Subject ◽  
Points Of View ◽  
Definition Of

In the administrative and legal science there is a refinement, change and expansion of the subject of the dynamic branch of administrative law, aimed at eliminating the resulting lag of legal theory from the legal reality. In our view, of the three basic categories that characterize the subject of administrative law, “public administration”, “executive power” and “administrativepublic activity”, the main generalization category is the category “administrative and public activities”. The phenomenon of the subject of administrative law refracts the problems and discussions inherent in the industry as a whole. In view of the existence of different points of view on the subject of administrative law, the legal science has not yet formulated a single definition of it. There is a tendency to overcome the conflict between different types of understanding, to bring together the positions of different concepts of understanding of administrative law in order to form a “universal” concept of it, to develop its common concept.

scholarly journals Characteristics of heat ceramics of Mordovian territory: on the example of the collection of Mordovian republican S. D. Erzia Fine Art Museum

2019 ◽  
Vol 11 (2) ◽  
pp. 222-231
Author(s):  
Andrey S. Barmenkov
Keyword(s):  
Comparative Analysis ◽  
Morphological Analysis ◽  
Fine Art ◽  
Art Museum ◽  
Maximum Extension ◽  
Different Types ◽  
The Subject ◽  
Functional Purpose

Introduction. The article is devoted to the description of pottery ceramics on Mordovian territory. The purpose of the article is to analyze the development of ceramics in Mordovian region. The object of the article is a collection of ceramics of Mordovian republican S.D. Erzia Fine Art Museum, the subject – the main features of the ceramics based on the morphological analysis of its exhibits. Materials and Methods. The material of the study was the results of the research of Russian scholars on ceramics of antiquity and modernity, as well as empirical materials presented by the ceramics funds of Mordovian republican S.D. Erzia Fine Art Museum. One of the main approaches implemented in the article is a comparative analysis of the exhibits based on the color of the shard. It allows the author to systematize utensils according to their functional purpose, and also to make an assumption about the various historical stages of the emergence of different types. Results and Discussion. The article systematizes the variety of forms of ceramics, reveals their quantitative relationships, the prevailing forms, and gives the comparative analysis of the existing forms. The classification of vessels was carried out in accordance with a number of criteria: the height and thickness of the neck, the design of the corolla cut, the diameter of the mouth and the maximum extension of the trunk, which allows one to draw conclusions about the similarity of the collection’s exhibits with other Mordоvian artefacts. Conclusion. It concludes about the existence of a certain standard in the production of ceramic dishes, and on the similarity of the studied ceramics and the collections of Russian monuments. Therefore, it states the preservation of local Mordovian pottery traditions in the course of wide interactions with Russian pottery ceramics.

scholarly journals The Utilization of Mobile Money Services in Small Scale Enterprises:A Case Study

2019 ◽  
Vol 4 (6) ◽  
Author(s):  
Suryakanthi Tangirala ◽  
Samuel Nlondiwa
Keyword(s):  
Mobile Phone ◽  
Service Providers ◽  
Small Scale ◽  
Small Enterprises ◽  
Mobile Money ◽  
Different Types ◽  
The Subject ◽  
Transactional Costs

Mobile money is an electronic wallet service that allows users to store, send and receive money using their mobile phone. This research is an effort to find out the adoption and utilization of mobile money services in small sized enterprises located in Gaborone, Botswana. Inevitably, other aspects such as different types of transactions carried out using mobile money services in small business, customer’s perception on quality of mobile money service providers, impeding factors of mobile money adoption are also studied for wider understanding of the subject. The findings of the study show that small enterprises use mobile money services to carryout transactions but the level of adoption is not significant. The study revealed that transactional costs and connectivity issues are major barriers of adoption of mobile money services. In conclusion the study recommended that the service providers must improve the connectivity issues and reduce transaction charges in order to increase the utilization of mobile money services

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