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Computational drug design

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https://www.readbyqxmd.com/read/28319781/systematic-study-of-imidazoles-inhibiting-ido1-via-the-integration-of-molecular-mechanics-and-quantum-mechanics-calculations
#1
Yi Zou, Fang Wang, Yan Wang, Wenjie Guo, Yihua Zhang, Qiang Xu, Yisheng Lai
Indoleamine 2,3-dioxygenase 1 (IDO1) is regarded as an attractive target for cancer immunotherapy. To rationalize the detailed interactions between IDO1 and its inhibitors at the atomic level, an integrated computational approach by combining molecular mechanics and quantum mechanics methods was employed in this report. Specifically, the binding modes of 20 inhibitors was initially investigated using the induced fit docking (IFD) protocol, which outperformed other two docking protocols in terms of correctly predicting ligand conformations...
March 14, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28315994/urgency-and-austerity-as-drivers-of-success
#2
Terry R Stouch
This piece describes the approach by which even a small CADD (Computer-Aided Drug Design) group with limited resources and limited time can achieve substantial success given short budgets and the compressed, urgent environment of a biotech. Some comparisons are made with CADD operations in big pharma.
March 18, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28315993/a-cadd-alog-of-strategies-in-pharma
#3
EDITORIAL
Wendy A Warr
A special issue on computer-aided drug design (CADD) strategies in pharma discusses how CADD groups in different environments work. Perspectives were collected from authors in 11 organizations: four big pharmaceutical companies, one major biotechnology company, one smaller biotech, one private pharmaceutical company, two contract research organizations (CROs), one university, and one that spans the breadth of big pharmaceutical companies and one smaller biotech.
March 18, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28303031/a-biologically-validated-hcv-e1e2-heterodimer-structural-model
#4
Matteo Castelli, Nicola Clementi, Jennifer Pfaff, Giuseppe A Sautto, Roberta A Diotti, Roberto Burioni, Benjamin J Doranz, Matteo Dal Peraro, Massimo Clementi, Nicasio Mancini
The design of vaccine strategies and the development of drugs targeting the early stages of Hepatitis C virus (HCV) infection are hampered by the lack of structural information about its surface glycoproteins E1 and E2, the two constituents of HCV entry machinery. Despite the recent crystal resolution of limited versions of both proteins in truncated form, a complete picture of the E1E2 complex is still missing. Here we combined deep computational analysis of E1E2 secondary, tertiary and quaternary structure with functional and immunological mutational analysis across E1E2 in order to propose an in silico model for the ectodomain of the E1E2 heterodimer...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28302551/role-of-structural-bioinformatics-in-drug-discovery-by-computational-snp-analysis-a-proposed-protocol-for-analyzing-variation-at-the-protein-level
#5
REVIEW
David K Brown, Özlem Tastan Bishop
With the completion of the human genome project at the beginning of the 21st century, the biological sciences entered an unprecedented age of data generation, and made its first steps toward an era of personalized medicine. This abundance of sequence data has led to the proliferation of numerous sequence-based techniques for associating variation with disease, such as genome-wide association studies and candidate gene association studies. However, these statistical methods do not provide an understanding of the functional effects of variation...
March 13, 2017: Global Heart
https://www.readbyqxmd.com/read/28299743/computational-approaches-to-matrix-metalloprotease-drug-design
#6
Tanya Singh, B Jayaram, Olayiwola Adedotun Adekoya
Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes required for homeostasis. These enzymes are an important class of drug targets as their over expression is associated with many disease states. Most of the inhibitors reported against this class of proteins have failed in clinical trials due to lack of specificity. In order to assist in drug design endeavors for MMP targets, a computationally tractable pathway is presented, comprising, (1) docking of small molecule inhibitors against the target MMPs, (2) derivation of quantum mechanical charges on the zinc ion in the active site and the amino acids coordinating with zinc including the inhibitor molecule, (3) molecular dynamics simulations on the docked ligand-MMP complexes, and (4) evaluation of binding affinities of the ligand-MMP complexes via an accurate scoring function for zinc containing metalloprotein-ligand complexes...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28298546/64cu-mm-302-positron-emission-tomography-quantifies-variability-of-enhanced-permeability-and-retention-of-nanoparticles-in-relation-to-treatment-response-in-patients-with-metastatic-breast-cancer
#7
Helen Lee, Anthony F Shields, Barry A Siegel, Kathy D Miller, Ian Krop, Cynthia X Ma, Patricia M LoRusso, Pamela N Munster, Karen Campbell, Daniel F Gaddy, Shannon C Leonard, Elena Geretti, Stephanie J Blocker, Dmitri B Kirpotin, Victor Moyo, Thomas J Wickham, Bart S Hendriks
PURPOSE: Therapeutic nanoparticles are designed to deliver their drug payloads through enhanced permeability and retention (EPR) in solid tumors. The extent of EPR and its variability in human tumors is highly debated and has been proposed as an explanation for variable responses to therapeutic nanoparticles in clinical studies. EXPERIMENTAL DESIGN: We assessed the EPR effect in patients using a 64Cu-labeled nanoparticle, 64Cu-MM-302 (64Cu-labeled HER2-targeted PEGylated liposomal doxorubicin), and imaging by Positron Emission Tomography/Computed Tomography (PET/CT)...
March 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28298524/novel-noncatalytic-substrate-selective-p38%C3%AE-specific-mapk-inhibitors-with-endothelial-stabilizing-and-anti-inflammatory-activity
#8
Nirav G Shah, Mohan E Tulapurkar, Aparna Ramarathnam, Amanda Brophy, Ramon Martinez, Kellie Hom, Theresa Hodges, Ramin Samadani, Ishwar S Singh, Alexander D MacKerell, Paul Shapiro, Jeffrey D Hasday
The p38 MAPK family is composed of four kinases of which p38α/MAPK14 is the major proinflammatory member. These kinases contribute to many inflammatory diseases, but the currently available p38 catalytic inhibitors (e.g., SB203580) are poorly effective and cause toxicity. We reasoned that the failure of catalytic p38 inhibitors may derive from their activity against noninflammatory p38 isoforms (e.g., p38β/MAPK11) and loss of all p38α-dependent responses, including anti-inflammatory, counterregulatory responses via mitogen- and stress-activated kinase (MSK) 1/2 and Smad3...
March 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28294055/therapeutic-molecular-and-computational-aspects-of-novel-monoamine-oxidase-mao-inhibitors
#9
M Ramesh, Yussif M Dokurugu, Michael D Thompson, Mahmoud Soliman
Due to the limited number of MAOs inhibitors in the clinic and several research efforts are aimed at the discovery of novel MAOs inhibitors. At present, high specificity and a reversible mode of inhibition of MAO-A/B are cited as desirable traits in drug discovery process. This will help to reduce the probability of causing target disruption and may increase the duration of action. Most of the existing MAO inhibitors lead to side effects due to lack of affinity and selectivity. Therefore, there is an urgent need to design novel, potent, reversible and selective inhibitors for MAO-A/B...
March 10, 2017: Combinatorial Chemistry & High Throughput Screening
https://www.readbyqxmd.com/read/28294048/computer-aided-structure-based-drug-design-approaches-for-the-discovery-of-new-anti-chikv-agents
#10
Surender Singh Jadav, Barij Nayan Sinha, Rolf Hilgenfeld, Venkatesan Jayaprakash
BACKGROUND: Chikungunya is a viral infection caused by Chikungunya virus (CHIKV), an arbovirus transmitted through mosquito (Aedes aegypti and Aedes albopictus) bite. The virus from sylvatic cycle in Africa mutated to new vector adaptation and became one of the major emerging and re-emerging viral infections in the past decade, affecting more than 40 countries. Efforts are being made by many researches to develop means to prevent and control the infection through vaccines and vector control strategy...
March 9, 2017: Current Computer-aided Drug Design
https://www.readbyqxmd.com/read/28292832/functional-organization-of-vestibulo-ocular-responses-in-abducens-motoneurons
#11
Haike Dietrich, Stefan Glasauer, Hans Straka
Vestibulo-ocular reflexes (VOR) are the dominating contributors to gaze stabilization in all vertebrates. During horizontal head movements, abducens motoneurons form the final element of the reflex arc that integrates visuo-vestibular inputs into temporally precise motor commands for the lateral rectus eye muscle. Here, we studied a possible differentiation of abducens motoneurons into subtypes by evaluating their morphology, discharge properties and synaptic pharmacology in semi-intact in vitro preparations of larval Xenopus laevis Extracellular nerve recordings during sinusoidal head motion revealed a continuum of resting rates and activation thresholds during vestibular stimulation...
March 14, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28291763/wonka-and-oommppaa-analysis-of-protein-ligand-interaction-data-to-direct-structure-based-drug-design
#12
Charlotte M Deane, Ian D Wall, Darren V S Green, Brian D Marsden, Anthony R Bradley
In this work, two freely available web-based interactive computational tools that facilitate the analysis and interpretation of protein-ligand interaction data are described. Firstly, WONKA, which assists in uncovering interesting and unusual features (for example residue motions) within ensembles of protein-ligand structures and enables the facile sharing of observations between scientists. Secondly, OOMMPPAA, which incorporates protein-ligand activity data with protein-ligand structural data using three-dimensional matched molecular pairs...
March 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28281230/identifying-the-interaction-of-vancomycin-with-novel-ph-responsive-lipids-as-antibacterial-biomaterials-via-accelerated-molecular-dynamics-and-binding-free-energy-calculations
#13
Shaimaa Ahmed, Suresh B Vepuri, Mahantesh Jadhav, Rahul S Kalhapure, Thirumala Govender
Nano-drug delivery systems have proven to be an efficient formulation tool to overcome the challenges with current antibiotics therapy and resistance. A series of pH-responsive lipid molecules were designed and synthesized for future liposomal formulation as a nano-drug delivery system for vancomycin at the infection site. The structures of these lipids differ from each other in respect of hydrocarbon tails: Lipid1, 2, 3 and 4 have stearic, oleic, linoleic, and linolenic acid hydrocarbon chains, respectively...
March 9, 2017: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28270198/large-scale-adverse-effects-related-to-treatment-evidence-standardization-laertes-an-open-scalable-system-for-linking-pharmacovigilance-evidence-sources-with-clinical-data
#14
(no author information available yet)
BACKGROUND: Integrating multiple sources of pharmacovigilance evidence has the potential to advance the science of safety signal detection and evaluation. In this regard, there is a need for more research on how to integrate multiple disparate evidence sources while making the evidence computable from a knowledge representation perspective (i.e., semantic enrichment). Existing frameworks suggest well-promising outcomes for such integration but employ a rather limited number of sources...
March 7, 2017: Journal of Biomedical Semantics
https://www.readbyqxmd.com/read/28270060/editorial-multi-target-in-computer-aided-drug-design-studies
#15
EDITORIAL
Luciana Scotti, Marcus T Scotti
No abstract text is available yet for this article.
2017: Current Drug Targets
https://www.readbyqxmd.com/read/28267554/is-gender-still-a-predisposing-factor-in-contrast-media-associated-adverse-drug-reactions-a-systematic-review-and-meta-analysis-of-randomized-trials-and-observational-studies
#16
Heeyoung Lee, Seungyeon Song, Yun-Kyoung Oh, WonKu Kang, Eunyoung Kim
OBJECTIVE: To evaluate the role of gender as a risk factor for developing contrast media-associated adverse drug reactions (CM-ADRs) by comparing the incidence of CM-ADR between male and female patients according to study design, ADR type, and computed tomography (CT) examination. MATERIAL AND METHODS: We systematically searched three electronic databases for eligible studies. In the studies included (n=18), we assessed effect estimates of the relative incidence of CM-ADR, analysed by experimental design, ADR type and CT examination...
April 2017: European Journal of Radiology
https://www.readbyqxmd.com/read/28266272/multiscale-molecular-simulations-applied-to-nucleic-acid-dendrimer-interactions-studies
#17
Fernando Danilo González-Nilo, Ingrid Araya-Durán, Valeria Márquez-Miranda
BACKGROUND: Dendrimers are monodisperse, regular, three-dimensional and small-scale macromolecules that can be used to release substances such as drugs, markers, and genetic material into the cells. Among these substances, nucleic acids such as plasmid DNA, antisense oligonucleotides (asODN), and small-interfering RNA (siRNA) are widely used as therapeutic macromolecules for the treatment and prevention of diverse diseases. Several studies were focused on the modification of dendrimers aiming to improve their affinity for nucleic acids and their ability to release nucleic acids inside the cells...
March 5, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28266020/insights-into-the-function-of-opioid-receptors-from-molecular-dynamics-simulations-of-available-crystal-structures
#18
REVIEW
Kristen A Marino, Yi Shang, Marta Filizola
The opioid receptors (ORs) are key targets in the treatment of acute and chronic pain, and the development of novel analgesics with reduced side effects is crucial in the search for more effective medications. The crystal structures of ORs have provided a wealth of knowledge on many aspects of OR pharmacology and function, including ligand binding poses, location of the sodium allosteric binding site, conformational changes associated with activation, and putative dimeric interfaces. These crystal structures also offer a starting point for molecular dynamics (MD) simulations to capture one aspect of drug design that static structures cannot resolve, namely protein dynamics...
March 7, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28263602/aldehyde-oxidase-mediated-metabolism-in-drug-like-molecules-a-combined-computational-and-experimental-study
#19
Yuan Xu, Liang Li, Yulan Wang, Jing Xing, Lei Zhou, Dafang Zhong, Xiaomin Luo, Hualiang Jiang, Kaixian Chen, Mingyue Zheng, Pan Deng, Xiaoyan Chen
Aldehyde oxidase (AOX) is an important drug-metabolizing enzyme. However, the current in vitro models for evaluating AOX metabolism are sometimes misleading, and preclinical animal models generally fail to predict human AOX-mediated metabolism. In this study, we report a combined computational and experimental investigation of drug-like molecules that are potential aldehyde oxidase substrates, of which multiple sites of metabolism (SOMs) mediated by AOX and their preferences for the reaction can be unambiguously identified...
March 6, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28260517/capi-computational-model-for-apicoplast-inhibitors-prediction-against-plasmodium-parasite
#20
Surabhi Dixit, Deepak Singla
Background Discovery of apicoplast as a drug target offers a new direction in the development of novel anti-malarial compounds, especially against the drug-resistant strains. Drugs such as azithromycin were reported to block the apicoplast development that leads to unusual phenotypes affecting the parasite. This phenomenon suggeststhat identification of new apicoplast inhibitors will aid in the anti-malarial drug discovery. Therefore, in this study, we developed a computational model to predict apicoplast inhibitors by applying state-of-the-art machine learning techniques...
March 1, 2017: Current Computer-aided Drug Design
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