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Computational drug design

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https://www.readbyqxmd.com/read/28453775/deconvoluting-kinase-inhibitor-induced-cardiotoxicity
#1
Sarah D Lamore, Ernst Ahlberg, Scott Boyer, Michelle L Lamb, Maria P Hortigon-Vinagre, Victor Rodriguez, Godfrey L Smith, Johanna Sagemark, Lars Carlsson, Stephanie M Bates, Allison L Choy, Jonna Stålring, Clay W Scott, Matthew F Peters
Many drugs designed to inhibit kinases have their clinical utility limited by cardiotoxicity-related label warnings or prescribing restrictions. While this liability is widely recognized, designing safer kinase inhibitors (KI) requires knowledge of the causative kinase(s). Efforts to unravel the kinases have encountered pharmacology with nearly prohibitive complexity. At therapeutically relevant concentrations, KIs show promiscuity distributed across the kinome. Here, to overcome this complexity, 65 KIs with known kinome-scale polypharmacology profiles were assessed for effects on cardiomyocyte beating...
April 26, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28453640/pioneering-topological-methods-for-network-based-drug-target-prediction-by-exploiting-a-brain-network-self-organization-theory
#2
Claudio Durán, Simone Daminelli, Josephine M Thomas, V Joachim Haupt, Michael Schroeder, Carlo Vittorio Cannistraci
The bipartite network representation of the drug-target interactions (DTIs) in a biosystem enhances understanding of the drugs' multifaceted action modes, suggests therapeutic switching for approved drugs and unveils possible side effects. As experimental testing of DTIs is costly and time-consuming, computational predictors are of great aid. Here, for the first time, state-of-the-art DTI supervised predictors custom-made in network biology were compared-using standard and innovative validation frameworks-with unsupervised pure topological-based models designed for general-purpose link prediction in bipartite networks...
April 26, 2017: Briefings in Bioinformatics
https://www.readbyqxmd.com/read/28453293/predicting-a-drug-s-membrane-permeability-a-computational-model-validated-with-in-vitro-permeability-assay-data
#3
Brian J Bennion, Nicholas A Be, Margaret Windy McNerney, Victoria Lao, Emma M Carlson, Carlos A Valdez, Michael A Malfatti, Heather A Enright, Tuan H Nguyen, Felice C Lightstone, Timothy S Carpenter
Membrane permeability is a key property to consider during the drug design process, and particularly vital when dealing with small molecules that have intracellular targets as their efficacy highly depends on their ability to cross the membrane. In this work, we describe the use of umbrella sampling Molecular Dynamics (MD) computational modeling to comprehensively assess the passive permeability profile of a range of compounds through a lipid bilayer. The model was initially calibrated through in vitro validation studies employing a Parallel Artificial Membrane Permeability Assay (PAMPA)...
April 28, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28446611/unraveling-amino-acid-residues-critical-for-allosteric-potentiation-of-%C3%AE-4-3-%C3%AE-2-2-type-nicotinic-acetylcholine-receptor-responses
#4
Ze-Jun Wang, Farah Deba, Tasnim S Mohamed, David C Chiara, Kara Ramos, Ayman K Hamouda
Neuronal nicotinic acetylcholine receptors (nAChRs) are promising drug targets to manage several neurological disorders and nicotine addiction. Growing evidence indicates that positive allosteric modulators (PAMs) of nAChRs improve pharmacological specificity by binding to unique sites present only in a subpopulation of nAChRs. Furthermore, nAChR PAMs such as NS9283 and CMPI have been shown to potentiate responses of (α4)3(β2)2 but not (α4)2(β2)3 nAChR isoforms. This selective potentiation underlines that the α4:α4 interface, which is present only in the (α4)3(β2)2 nAChR, is an important and promising drug target...
April 26, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28443252/open-label-phase-ii-clinical-trial-in-75-patients-with-advanced-hepatocellular-carcinoma-receiving-daily-dose-of-tableted-liver-cancer-vaccine-hepcortespenlisimut-l
#5
Marina G Tarakanovskaya, Jigjidsuren Chinburen, Purev Batchuluun, Chogsom Munkhzaya, Genden Purevsuren, Dorjiin Dandii, Tsogkhuu Hulan, Dandii Oyungerel, Galyna A Kutsyna, Alan A Reid, Vika Borisova, Allen I Bain, Vichai Jirathitikal, Aldar S Bourinbaiar
BACKGROUND: An increasing number of studies is now devoted to immunotherapy of cancer. We evaluated the clinical benefit of hepcortespenlisimut-L (Hepko-V5 [formerly known as V5])-an oral therapeutic vaccine designated by the United States Food and Drug Administration (FDA) as an orphan drug for treatment of hepatocellular carcinoma (HCC). V5 was initially developed by us in 2002 to treat hepatitis B or C viral infections and liver cirrhosis. METHODS: The outcome of open-label Phase II trial of daily dose of V5 pill was analyzed retrospectively...
2017: Journal of Hepatocellular Carcinoma
https://www.readbyqxmd.com/read/28441481/best-practices-of-computer-aided-drug-discovery-cadd-lessons-learned-from-the-development-of-a-preclinical-candidate-for-prostate-cancer-with-a-new-mechanism-of-action
#6
Fuqiang Ban, Kush Dalal, Huifang Li, Eric LeBlanc, Paul S Rennie, Artem Cherkasov
Small-molecule drug design is a complex and iterative decision-making process relying on pre-existing knowledge and driven by experimental data. Low molecular weight chemicals represent an attractive therapeutic option as they are readily accessible to organic synthesis and can easily be characterized.1 Their potency, as well as pharmacokinetic and pharmacodynamic properties can be systematically and rationally investigated, and ultimately optimized via expert science behind medicinal chemistry and methods of computer-aided drug design (CADD)...
April 25, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28436422/rational-design-of-non-resistant-targeted-cancer-therapies
#7
Francisco Martínez-Jiménez, John P Overington, Bissan Al-Lazikani, Marc A Marti-Renom
Drug resistance is one of the major problems in targeted cancer therapy. A major cause of resistance is changes in the amino acids that form the drug-target binding site. Despite of the numerous efforts made to individually understand and overcome these mutations, there is a lack of comprehensive analysis of the mutational landscape that can prospectively estimate drug-resistance mutations. Here we describe and computationally validate a framework that combines the cancer-specific likelihood with the resistance impact to enable the detection of single point mutations with the highest chance to be responsible of resistance to a particular targeted cancer therapy...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28434763/computer-aided-discovery-of-two-novel-chalcone-like-compounds-active-and-selective-against-leishmania-infantum
#8
Marcelo N Gomes, Laura M Alcântara, Bruno J Neves, Cleber C Melo-Filho, Lucio H Freitas-Junior, Carolina B Moraes, Rui Ma, Scott G Franzblau, Eugene Muratov, Carolina Horta Andrade
Leishmaniasis are infectious diseases caused by parasites of genus Leishmania that affect affects 12 million people in 98 countries mainly in Africa, Asia, and Latin America. Effective treatments for this disease are urgently needed. In this study, we present a computer-aided approach to investigate a set of 32 recently synthesized chalcone and chalcone-like compounds to act as antileishmanial agents. As a result, nine most promising compounds and three potentially inactive compounds were experimentally evaluated against Leishmania infantum amastigotes and mammalian cells...
April 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28430779/a-coevolution-analysis-for-identifying-protein-protein-interactions-by-fourier-transform
#9
Changchuan Yin, Stephen S-T Yau
Protein-protein interactions (PPIs) play key roles in life processes, such as signal transduction, transcription regulations, and immune response, etc. Identification of PPIs enables better understanding of the functional networks within a cell. Common experimental methods for identifying PPIs are time consuming and expensive. However, recent developments in computational approaches for inferring PPIs from protein sequences based on coevolution theory avoid these problems. In the coevolution theory model, interacted proteins may show coevolutionary mutations and have similar phylogenetic trees...
2017: PloS One
https://www.readbyqxmd.com/read/28427307/molecular-dynamics-thermodynamic-and-mutational-binding-studies-for-tumor-specific-lyp-1-in-complex-with-p32
#10
Selin Seda Timur, Gözde Yalçın, Özge Çevik, Cenk Andaç, R Neslihan Gürsoy
Recent studies in tumor homing peptides have shown the specificity of LyP-1 (CGNKRTRGC) to tumor lymphatics. In this present work, we evaluated the possible interactions between cyclic LyP-1 and its receptor, p32, with molecular dynamics and docking studies in order to lead the design of novel LyP-1 derivatives, which could bind to p32 more effectively and perform enhanced antitumor effect. The total binding enthalpy energies have been obtained by MM-PBSA thermodynamic computations and the favorability of p32...
April 21, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28427017/aromatase-inhibitors-and-apoptotic-inducers-design-synthesis-anticancer-activity-and-molecular-modeling-studies-of-novel-phenothiazine-derivatives-carrying-sulfonamide-moiety-as-hybrid-molecules
#11
Mostafa M Ghorab, Mansour S Alsaid, Nermin Samir, Ghada A Abdel-Latif, Aiten M Soliman, Fatma A Ragab, Dalal A Abou El Ella
Hybrid molecules are used as anticancer agents to improve effectiveness and diminish drug resistance. So, the current study aimed to introduce twenty novel phenothiazine sulfonamide hybrids 5-22, 24 and 25 of promising anticancer activity. Compounds 11 and 13 revealed more potent anticancer properties (IC50 8.1 and 8.8 μM) than that of the reference drug (doxorubicin, IC50 = 9.8 μM) against human breast cancer cell line (T47D). To determine the mechanism of their anticancer activity, compounds 5, 6, 7, 11, 13, 14, 16, 17, 19 and 22 that showed promising activity on T47D, were evaluated for their aromatase inhibitory effect...
April 15, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28426203/tyrosine-kinase-activation-and-conformational-flexibility-lessons-from-src-family-tyrosine-kinases
#12
Yilin Meng, Matthew P Pond, Benoît Roux
Protein kinases are enzymes that catalyze the covalent transfer of the γ-phosphate of an adenosine triphosphate (ATP) molecule onto a tyrosine, serine, threonine, or histidine residue in the substrate and thus send a chemical signal to networks of downstream proteins. They are important cellular signaling enzymes that regulate cell growth, proliferation, metabolism, differentiation, and migration. Unregulated protein kinase activity is often associated with a wide range of diseases, therefore making protein kinases major therapeutic targets...
April 20, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28425718/testing-high-concentrations-of-membrane-active-antibiotic-chlorhexidine-via-computational-titration-and-calorimetry
#13
Brad Van Oosten, Drew Marquardt, Thad A Harroun
Coarse grained strategies for membrane simulations are designed to increase the time and length scales of molecular dynamics simulations. For membrane active antibiotics, the concentration dependence of their action presents a tremendous challenge in simulation scale. In this study we examine the effects of concentration for the popular membrane active antibacterial drug chlorhexidine. It presents an interesting biophysical modelling test, where from experimental experience we know that model membranes of DMPC can absorb very high quantities of the drug without disruption...
April 20, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28423275/single-or-multiple-access-channels-to-the-cyp450s-active-site-an-answer-from-free-energy-simulations-of-the-human-aromatase-enzyme
#14
Alessandra Magistrato, Jacopo Sgrignani, Rolf Krause, Andrea Cavalli
Cytochromes P450 (CYP450s), in particular, CYP19A1 and CYP17A1, are key clinical targets of breast and prostate anticancer therapies, critical players in drug metabolism, and their overexpression in tumors is associated with drug resistance. In these enzymes, ligand (substrates, drugs) metabolism occurs in deeply buried active sites accessible only via several grueling channels, whose exact biological role remains unclear. Gaining direct insights on the mechanism by which ligands travel in and out is becoming increasingly important given that channels are involved in the modulation of binding/dissociation kinetics and the specificity of ligands toward a CYP450...
April 24, 2017: Journal of Physical Chemistry Letters
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
#15
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/28413946/kinetics-of-ligand-binding-through-advanced-computational-approaches-a-review
#16
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/28413096/implementing-webgl-and-html5-in-macromolecular-visualization-and-modern-computer-aided-drug-design
#17
REVIEW
Shuguang Yuan, H C Stephen Chan, Zhenquan Hu
Web browsers have long been recognized as potential platforms for remote macromolecule visualization. However, the difficulty in transferring large-scale data to clients and the lack of native support for hardware-accelerated applications in the local browser undermine the feasibility of such utilities. With the introduction of WebGL and HTML5 technologies in recent years, it is now possible to exploit the power of a graphics-processing unit (GPU) from a browser without any third-party plugin. Many new tools have been developed for biological molecule visualization and modern drug discovery...
April 13, 2017: Trends in Biotechnology
https://www.readbyqxmd.com/read/28410930/ligand-diffusion-in-proteins-via-enhanced-sampling-in-molecular-dynamics
#18
REVIEW
J Rydzewski, W Nowak
Computational simulations in biophysics describe the dynamics and functions of biological macromolecules at the atomic level. Among motions particularly important for life are the transport processes in heterogeneous media. The process of ligand diffusion inside proteins is an example of a complex rare event that can be modeled using molecular dynamics simulations. The study of physical interactions between a ligand and its biological target is of paramount importance for the design of novel drugs and enzymes...
April 1, 2017: Physics of Life Reviews
https://www.readbyqxmd.com/read/28409029/biophysical-approaches-facilitate-computational-drug-discovery-for-atp-binding-cassette-proteins
#19
REVIEW
Steven V Molinski, Zoltán Bozóky, Surtaj H Iram, Saumel Ahmadi
Although membrane proteins represent most therapeutically relevant drug targets, the availability of atomic resolution structures for this class of proteins has been limited. Structural characterization has been hampered by the biophysical nature of these polytopic transporters, receptors, and channels, and recent innovations to in vitro techniques aim to mitigate these challenges. One such class of membrane proteins, the ATP-binding cassette (ABC) superfamily, are broadly expressed throughout the human body, required for normal physiology and disease-causing when mutated, yet lacks sufficient structural representation in the Protein Data Bank...
2017: International Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28408471/genomes-structural-biology-and-drug-discovery-combating-the-impacts-of-mutations-in-genetic-disease-and-antibiotic-resistance
#20
REVIEW
Arun Prasad Pandurangan, David B Ascher, Sherine E Thomas, Tom L Blundell
For over four decades structural biology has been used to understand the mechanisms of disease, and structure-guided approaches have demonstrated clearly that they can contribute to many aspects of early drug discovery, both computationally and experimentally. Structure can also inform our understanding of impacts of mutations in human genetic diseases and drug resistance in cancers and infectious diseases. We discuss the ways that structural insights might be useful in both repurposing off-licence drugs and guide the design of new molecules that might be less susceptible to drug resistance in the future...
April 15, 2017: Biochemical Society Transactions
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