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Current Topics in Medicinal Chemistry

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https://www.readbyqxmd.com/read/28413955/drug-discovery-and-molecular-dynamics-methods-applications-and-perspective-beyond-the-second-timescale
#1
Gerard Martínez-Rosell, Toni Giorgino, Matt J Harvey, Gianni de Fabritiis
Bio-molecular dynamics (MD) simulations based on graphical processing units (GPUs) were first released to the public in the early 2009 with the code ACEMD. Almost 8 years after, applications now encompass a broad range of molecular studies, while throughput improvements have opened the way to millisecond sampling timescales. Based on an extrapolation of the amount of sampling in published literature, the second timescale will be reached by the year 2022, and therefore we predict that molecular dynamics is going to become one of the main tools in drug discovery in both academia and industry...
April 14, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28413954/computational-models-for-understanding-of-structure-function-and-pharmacology-of-the-cardiac-potassium-channel-kv11-1-herg
#2
Sören Wacker, Sergei Yu Noskov, Laura L Perissinotti
The rapid delayed rectifier current IKr is one of the major K+ currents involved into repolarization of the human cardiac action potential. Various inherited or drug-induced forms of the long QT syndrome (LQTS) in humans are linked to functional and structural modifications in the IKr conducting channels. IKr is carried by the potassium channel Kv11.1 encoded by the gene KCNH2 (commonly referred to as human ether-a-go-go-related gene or hERG) [1][2]. The first necessary step for predicting emergent drug effects on the heart is determining and modeling the binding thermodynamics and kinetics of primary and major off-target drug interactions with subcellular targets...
April 14, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28413953/calculating-water-thermodynamics-in-the-binding-site-of-proteins-applications-of-watermap-to-drug-discovery
#3
Daniel Cappel, Woody Sherman, Thijs Beuming
The ability to accurately characterize the solvation properties (water locations and thermodynamics) of biomolecules is of great importance to drug discovery. While crystallography, NMR, and other experimental techniques can assist in determining the structure of water networks in proteins and protein-ligand complexes, most water molecules are not fully resolved and accurately placed. Furthermore, understanding the energetic effects of solvation and desolvation on binding requires an analysis of the thermodynamic properties of solvent involved in the interaction between ligands and proteins...
April 14, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28413952/building-new-bridges-between-in-vitro-and-in-vivo-in-early-drug-discovery-where-molecular-modeling-meets-systems-biology
#4
Robert A Pearlstein, Daniel J J McKay, Viktor Hornak, Callum Dickson, Andrei Golosov, Tyler Harrison, Camilo Velez-Vega, José Duca
Cellular drug targets exist within networked function generating systems whose constituent molecular species undergo dynamic interdependent non-equilibrium state transitions in response to specific perturbations (i.e. inputs). Cellular phenotypic behaviors are manifest through the integrated behaviors of such networks. However, in vitro data are frequently measured and/or interpreted with empirical equilibrium or steady state models (e.g. Hill, Michaelis-Menten, Briggs-Haldane) relevant to isolated target populations...
April 14, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28413951/an-unprecedented-revolution-in-medicinal-chemistry-driven-by-the-progress-of-biological-science
#5
Kuo-Chen Chou
The eternal or ultimate goal of medicinal chemistry is to find most effective ways to treat various diseases and extend human beings' life as long as possible. Human being is a biological entity. To realize such an ultimate goal, the inputs or breakthroughs from the advances in biological science are no doubt most important that may even drive medicinal science into a revolution. In this review article, we are to address this from several different angles.
April 14, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28413950/a-critical-review-of-validation-blind-testing-and-real-world-use-of-alchemical-protein-ligand-binding-free-energy-calculations
#6
Robert Abel, Lingle Wang, David L Mobley, Rich A Friesner
Protein-ligand binding is among the most fundamental phenomena underlying all molecular biology, and a greater ability to more accurately and robustly predict the binding free energy of a small molecule ligand for its cognate protein is expected to have vast consequences for improving the efficiency of pharmaceutical drug discovery. We here briefly review a number of scientific and technical advances that have enabled alchemical free energy calculations to recently emerge as a preferred approach, and critically consider proper validation and effective use of these techniques...
April 14, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28413949/the-intrinsic-relationship-between-structure-and-function-of-the-sialyltransferase-st8sia-family-members
#7
Ri-Bo Huang, D Cheng, Bo Lu, S M Liao, Frederic A Troy Ii, Guo-Ping Zhou
As a subset of glycosyltransferases, the family of sialyltransferases catalyze transfer of sialic acid (Sia) residues to terminal non-reducing positions on oligosaccharide chains of glycoproteins and glycolipids, utilizing CMP-Neu5Ac as the activated sugar nucleotide donor. In the four known sialyltransferase families (ST3Gal, ST6Gal, ST6GalNAc and ST8Sia), the ST8Sia family catalyzes synthesis of si,8-linked sialic/polysialic acid (polySia) chains according to their acceptor specificity. We have determined 3D structural models of the ST8Sia family members, designated ST8Sia I(1), II(2), IV(4), V(5), and VI(6) using the Phyre2 server...
April 14, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28413948/some-remarks-on-prediction-of-drug-target-interaction-with-network-models
#8
Shao-Wu Zhang, Xiao-Ying Yan
System-level understanding of the relationships between drugs and targets is very important for enhancing drug research, especially for drug function repositioning. The experimental methods used to determine drug-target interactions are usually time-consuming, tedious and expensive, and sometimes lack reproducibility. Thus, it is highly desired to develop computational methods for efficiently and effectively analyzing and detecting new drug-target interaction pairs. With the explosive growth of different types of omics data, such as genome, pharmacology, phenotypic, and other kinds of molecular networks, numerous computational approaches have been developed to predict drug-target interactions (DTI)...
April 14, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28413947/novel-signaling-interface-constituted-with-membrane-receptor-like-kinases-emerged-from-the-study-of-interaction-and-transphosphorylation-of-bri1-and-bak1
#9
Cheng Li, Shan Zhang, Xiaofeng Wang
BRI1 and BAK1 are Receptor-Like Kinases (RLKs), one of the largest gene families in plants participating in various cell signal transduction from cell surface to cytoplasm with oligomerization and phosphorylation to regulate plant growth, development, immunity, and environmental responses. Based on the recent investigations on the BRI1 and BAK1 and other RLKs involving in the receptor complex formation, trans phosphorylation, phosphorylation sites identification, downstream substrates identification, and so on, it is recovered that the receptors oligomerization and phosphorylation integrate multiple distinct signaling to realize signaling modulation, divergence, convergence, and specificity...
April 14, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28413946/kinetics-of-ligand-binding-through-advanced-computational-approaches-a-review
#10
Alex Dickson, Pratyush Tiwary, Harish Vashisth
Ligand residence times and binding rates have been found to be useful quantities to consider during drug design. The underlying structural and dynamic determinants of these kinetic quantities are difficult to discern. Driven by developments in computational hardware and simulation methodologies, molecular dynamics (MD) studies of full binding and unbinding pathways have emerged recently, showing these structural and dynamic determinants in atomic detail. However, the long timescales related to drug binding and release are still prohibitive to conventional MD simulation...
April 14, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28403796/riboswitches-as-potential-targets-for-the-development-of-anti-biofilm-drugs
#11
José A Reyes-Darias, Tino Krell
In nature, bacteria can exist as single motile cells or as sessile cellular community, known as microbial biofilms. Bacteria within biofilms are embedded in a self-produced extracellular matrix that makes them more resistant to antibiotic treatment and responses of the host immune system. Microbial biofilms are very important in medicine since they are associated with several human diseases such as dental caries, periodontitis, otitis media, infective endocarditis, infectious kidney stones, osteomyelitis or prostatitis...
April 7, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28366137/critical-role-of-computer-simulations-in-drug-discovery-and-development
#12
Prachi Srivastava, Anshul Tiwari
The last couple of decades is witnessed that an amalgamation of multidisciplinary branches of science come together in the form of 'Bioinformatics' and made a substantial impact on the drug designing process. The applicability of Bioinformatics approaches has been able to reduce the overall cost and time of drug discovery and development. The computer aided drug designing system (CADDS) using extensive applicability of Bioinformatics has been recognized as one step ahead to carry out the primary high throughput virtual screening as an economically viable solution to the problem...
April 3, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28359251/applying-knowledge-of-enzyme-biochemistry-in-prediction-of-functional-sites-for-aiding-drug-discovery
#13
Priyadarshini P Pai, Sukanta Mondal
Enzymes are biological catalysts that play an important role in determining the patterns of chemical transformations pertaining to life. Many milestones have been achieved in unraveling the mechanisms in which the enzymes orchestrate various cellular processes using experimental and computational approaches. Experimental studies generating nearly all possible mutations of target enzymes have been aided by rapid computational approaches aiming at enzyme functional classification, understanding domain organization, functional site identification...
March 29, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28356000/new-achievements-in-bioinformatics-prediction-of-post-translational-modification-of-proteins
#14
Hassan Mohabatkar, Parisa Rabiei, Masoomeh Alamdaran
Post translational modification (PTM) is one of the critical levels in regulation of gene expression that determines the fate of proteins after translation in eukaryotic cells. Since the detection of PTM sites in proteins is useful for diagnosis and prevention of diseases, numerous web-tool predictors are introduced to predict various types of PTMs. In this paper, an attempt is made to summarize a number of server predictors for prediction of PTM sites.
March 28, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28355999/can-ligands-of-different-functional-types-induce-distinct-dynamics-in-g-protein-coupled-receptors
#15
Yu-Hsuan Chen, Jung-Hsin Lin
G protein-coupled receptors (GPCRs) are the most common therapeutic targets for drug discovery by the pharmaceutical industries. Since 2007, several three-dimensional X-ray crystallographic structures of ligand-activated GPCRs have been determined in their agonist-bound or inverse agonist-bound states, providing a wealth of fundamental resources for the investigation of the atomic-level mechanism of receptor activation and deactivation. A number of computational methods, such as conventional and enhanced sampling molecular dynamic (MD) simulations have been applied to investigate the receptor dynamics bound with ligands of different functional types (i...
March 28, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28270087/heterocyclic-analogues-as-kinase-inhibitors-a-focus-review
#16
Vipin Kumar, Raj Kamal, Vikas Sharma
Role of kinase inhibitors in various diseases is well established and discovery of imatinib opens up new paradigms in kinase inhibition. Furthermore, presence of heterocyclic moiety in a kinase inhibitor seems to be essential now. However, the potential of a single heterocyclic moiety was discussed in variety of reviews but a focus review considering the potential of different heterocyclic moieties is unavailable. Based on this, we classify prospective kinase inhibitors on the basis of number of heterocyclic moieties present and summarize the prospective kinase inhibitors...
March 7, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28270086/therapeutic-implications-of-superoxide-dismutase-and-its-importance-in-kinase-drug-discovery
#17
Nameet Kaur, Arun Kumar Sharma, Adeeba Shakeel, Vipin Kumar, Aarti Singh, Apoorv Gupta, Deepa Suhag, Satyendra K Rajput, Monalisa Mukherjee
In recent years, several scientific investigations have reported the therapeutic implications of superoxide dismutase (SOD) against oxidative stress and -induced pathology in clinical and preclinical trials. Indeed, various kinase, molecular signaling and physiological process has altered by reactive oxygen species. In spite of the abundant available literature reports, patents, clinical trials and commercialized products, the therapeutic application of SOD as a potential drug still remains unclear. Owing to the technical challenges associated with the utilization of SOD as a drug, we revisited the structural arrangement and cellular signaling, significant association with kinase which exploring the new target sites and introduction of new formulation strategies such as gene modulation, nano-formulations and click chemistry is a prerequisite...
March 7, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28260508/nitrone-derivatives-as-therapeutics-from-chemical-modification-to-specific-targeting
#18
Grégory Durand, Burkhard Poeggeler, Marie Rosselin
Nitrones have been extensively used for the detection of transient free radicals using electron paramagnetic resonance. Since the mid-80's, nitrones have also been widely used as protective agents against oxidative stress in several biological models. Due to the high potency of nitrones, there has been extensive research on the development of derivatives with improved biological and spin trapping properties as well as enhanced intra-cellular compartmentalization. The chemical and pharmacological properties of nitrones depend mainly on the connectivity as well as on the nature and the position of the substituents on the nitrone group...
March 3, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28240184/from-protein-structure-to-small-molecules-recent-advances-and-applications-to-fragment-based-drug-discovery
#19
Leonardo G Ferreira, Adriano D Andricopulo
Fragment-based drug discovery (FBDD) is a broadly used strategy in structure-guided ligand design, whereby low-molecular weight hits move from lead-like to drug-like compounds. Over the past 15 years, an increasingly important role of the integration of these strategies into industrial and academic research platforms has been successfully established, allowing outstanding contributions to drug discovery. One important factor for the current prominence of FBDD is the better coverage of the chemical space provided by fragment-like libraries...
February 24, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28240183/influenza-a-virus-nucleoprotein-a-highly-conserved-multi-functional-viral-protein-as-a-hot-antiviral-drug-target
#20
Yanmei Hu, Hannah Sneyd, Raphael Dekant, Jun Wang
Prevention and treatment of influenza virus infection is an ongoing unmet medical need. Each year, thousands of deaths and millions of hospitalizations are attributed to influenza virus infection, which poses a tremendous health and economic burden to the society. Aside from the annual influenza season, influenza viruses also lead to occasional influenza pandemics as a result of emerging or re-emerging influenza strains. Influenza viruses are RNA viruses that exist in quasispecies, meaning that they have a very diverse genetic background...
February 24, 2017: Current Topics in Medicinal Chemistry
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