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Computational drug design

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https://www.readbyqxmd.com/read/28730499/target-inhibition-maps-based-on-responses-to-kinase-inhibitors
#1
Noah Berlow, Ranadip Pal
The prediction of tumor sensitivity to targeted drugs remains a major challenge in the design of optimal therapeutic strategies. This chapter presents a computational modeling approach to infer target inhibition maps based on responses of the tumor culture to a range of kinase inhibitors. The kinase inhibition profiles of the targeted drugs and the functional responses are utilized to infer potential tumor proliferation circuits that can assist in generation of synergistic drug combinations.
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28728979/ploc-mvirus-predict-subcellular-localization-of-multi-location-virus-proteins-via-incorporating-the-optimal-go-information-into-general-pseaac
#2
Xiang Cheng, Xuan Xiao, Kuo-Chen Chou
Knowledge of subcellular locations of proteins is crucially important for in-depth understanding their functions in a cell. With the explosive growth of protein sequences generated in the postgenomic age, it is highly demanded to develop computational tools for timely annotating their subcellular locations based on the sequence information alone. The current study is focused on virus proteins. Although considerable efforts have been made in this regard, the problem is far from being solved yet. Most existing methods can be used to deal with single-location proteins only...
July 17, 2017: Gene
https://www.readbyqxmd.com/read/28725482/systems-biology-driving-drug-development-from-design-to-the-clinical-testing-of-the-anti-erbb3-antibody-seribantumab-mm-121
#3
REVIEW
Birgit Schoeberl, Art Kudla, Kristina Masson, Ashish Kalra, Michael Curley, Gregory Finn, Emily Pace, Brian Harms, Jaeyeon Kim, Jeff Kearns, Aaron Fulgham, Olga Burenkova, Viara Grantcharova, Defne Yarar, Violette Paragas, Jonathan Fitzgerald, Marisa Wainszelbaum, Kip West, Sara Mathews, Rachel Nering, Bambang Adiwijaya, Gabriela Garcia, Bill Kubasek, Victor Moyo, Akos Czibere, Ulrik B Nielsen, Gavin MacBeath
The ErbB family of receptor tyrosine kinases comprises four members: epidermal growth factor receptor (EGFR/ErbB1), human EGFR 2 (HER2/ErbB2), ErbB3/HER3, and ErbB4/HER4. The first two members of this family, EGFR and HER2, have been implicated in tumorigenesis and cancer progression for several decades, and numerous drugs have now been approved that target these two proteins. Less attention, however, has been paid to the role of this family in mediating cancer cell survival and drug tolerance. To better understand the complex signal transduction network triggered by the ErbB receptor family, we built a computational model that quantitatively captures the dynamics of ErbB signaling...
2017: NPJ Systems Biology and Applications
https://www.readbyqxmd.com/read/28724352/a-permutation-based-non-parametric-analysis-of-crispr-screen-data
#4
Gaoxiang Jia, Xinlei Wang, Guanghua Xiao
BACKGROUND: Clustered regularly-interspaced short palindromic repeats (CRISPR) screens are usually implemented in cultured cells to identify genes with critical functions. Although several methods have been developed or adapted to analyze CRISPR screening data, no single specific algorithm has gained popularity. Thus, rigorous procedures are needed to overcome the shortcomings of existing algorithms. METHODS: We developed a Permutation-Based Non-Parametric Analysis (PBNPA) algorithm, which computes p-values at the gene level by permuting sgRNA labels, and thus it avoids restrictive distributional assumptions...
July 19, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28723151/fusion-of-structure-and-ligand-based-methods-for-identification-of-novel-cdk2-inhibitors
#5
Priya Mahajan, Gousia Chashoo, Monika Gupta, Amit Kumar, Parvinder Pal Singh, Amit Nargotra
Cyclin dependent kinases plays a central role in cell cycle regulation which makes them a promising target with multifarious therapeutic potential. CDK2 regulates various events of the eukaryotic cell division cycle and the pharmacological evidences indicated that over expression of CDK2 causes abnormal cell-cycle regulation, which was directly associated with hyper proliferation of cancer cells. Therefore, CDK2 is regarded as a potential target molecule for anti-cancer medication. Thus to decline CDK2 activity by potential lead compounds has proved to be an effective treatment for cancer...
July 19, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28720874/knowledge-transfer-learning-for-prediction-of-matrix-metalloprotease-substrate-cleavage-sites
#6
Yanan Wang, Jiangning Song, Tatiana T Marquez-Lago, André Leier, Chen Li, Trevor Lithgow, Geoffrey I Webb, Hong-Bin Shen
Matrix Metalloproteases (MMPs) are an important family of proteases that play crucial roles in key cellular and disease processes. Therefore, MMPs constitute important targets for drug design, development and delivery. Advanced proteomic technologies have identified type-specific target substrates; however, the complete repertoire of MMP substrates remains uncharacterized. Indeed, computational prediction of substrate-cleavage sites associated with MMPs is a challenging problem. This holds especially true when considering MMPs with few experimentally verified cleavage sites, such as for MMP-2, -3, -7, and -8...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28720122/enhance-the-performance-of-current-scoring-functions-with-the-aid-of-3d-protein-ligand-interaction-fingerprints
#7
Jie Liu, Minyi Su, Zhihai Liu, Jie Li, Yan Li, Renxiao Wang
BACKGROUND: In structure-based drug design, binding affinity prediction remains as a challenging goal for current scoring functions. Development of target-biased scoring functions provides a new possibility for tackling this problem, but this approach is also associated with certain technical difficulties. We previously reported the Knowledge-Guided Scoring (KGS) method as an alternative approach (BMC Bioinformatics, 2010, 11, 193-208). The key idea is to compute the binding affinity of a given protein-ligand complex based on the known binding data of an appropriate reference complex, so the error in binding affinity prediction can be reduced effectively...
July 18, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28718646/exploring-the-relationship-between-nicotinic-acetylcholine-receptor-ligand-size-efficiency-efficacy-and-c-loop-opening
#8
Qianyun Ma, Han-Shen Tae, Guanzhao Wu, Tao Jiang, Rilei Yu
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels mediating fundamental physiological activities in the nervous system, and have become important targets for drug design. For a long time, the acetylcholine binding protein (AChBP) has been used as surrogate to study the nAChR structure-function. Taking advantage of more than 100 AChBP crystal structures in the Protein DataBank (PDB), we explored the relationship between the size, efficiency and efficacy of nAChR ligands and the C-loop movement...
July 18, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28718049/good-things-in-small-packages-an-innovative-delivery-approach-for-inhaled-insulin
#9
James B Fink, Lisa Molloy, John S Patton, Valdecir Castor Galindo-Filho, Jacqueline de Melo Barcelar, Luciana Alcoforado, Simone Cristina Soares Brandão, Armèle Dornelas de Andrade
PURPOSE: The design development of a small, hand held, battery operated, breath actuated inhaler as a drug/device platform for inhaled insulin posed a number of technical challenges. Our goal was to optimize lung deposition and distribution with aerosol generators producing 3-6 μm particle size distribution. METHODS: In silico modeling with computational fluid dynamics (CFD) and in vitro testing of device components were assessed using an Alberta idealized adult airway (Copley, UK) to optimize mouthpiece and aerosol path design for dose delivered distal to the trachea...
July 17, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28716510/evaluation-of-in-vivo-and-in-vitro-models-of-toxicity-by-comparison-of-toxicogenomics-data-with-the-literature
#10
Katerina Taškova, Jean-Fred Fontaine, Ralf Mrowka, Miguel A Andrade-Navarro
Toxicity affecting humans is studied by observing the effects of chemical substances in animal organisms (in vivo) or in animal and human cultivated cell lines (in vitro). Toxicogenomics studies collect gene expression profiles and histopathology assessment data for hundreds of drugs and pollutants in standardized experimental designs using different model systems. These data are an invaluable source for analyzing genome-wide drug response in biological systems. However, a problem remains that is how to evaluate the suitability of heterogeneous in vitro and in vivo systems to model the many different aspects of human toxicity...
July 14, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28713017/intracellular-co-delivery-of-sr-ion-and-phenamil-drug-through-mesoporous-bioglass-nanocarriers-synergizes-bmp-signaling-and-tissue-mineralization
#11
Jung-Hwan Lee, Nandin Mandakhbayar, Ahmed El-Fiqi, Haw-Won Kim
Inducing differentiation and maturation of resident multipotent stem cells (MSCs) is an important strategy to regenerate hard tissues in mal-calcification conditions. Here we explore a co-delivery approach of therapeutic molecules comprised of ion and drug through a mesoporous bioglass nanoparticle (MBN) for this purpose. Recently, MBN has offered unique potential as a nanocarrier for hard tissues, in terms of high mesoporosity, bone bioactivity (and possibly degradability), tunable delivery of biomolecules, and ionic modification...
July 13, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28708399/development-and-validation-of-a-computational-model-ensemble-for-the-early-detection-of-bcrp-abcg2-substrates-during-the-drug-design-stage
#12
Melisa Edith Gantner, Roxana Noemí Peroni, Juan Francisco Morales, María Luisa Villalba, María Esperanza Ruiz, Alan Talevi
Breast Cancer Resistance Protein (BCRP) is an ATP-dependent efflux transporter linked to the multidrug resistance phenomenon in many diseases such as epilepsy and cancer, and a potential source of drug interactions. For those reasons, the early identification of substrates and non-substrates of this transporter during the drug discovery stage is of great interest. We have developed a computational non-linear model ensemble based on conformational independent molecular descriptors using a combined strategy of genetic algorithms, J48 decision tree classifiers and data fusion...
July 14, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28707592/rational-drug-design-of-antineoplastic-agents-using-3d-qsar-cheminformatic-and-virtual-screening-approaches
#13
Jelica Vucicevic, Katarina Nikolic, John B O Mitchell
BACKGROUND: Computer-Aided Drug Design has strongly accelerated the development of novel antineoplastic agents by helping in the hit identification, optimization, and evaluation. RESULTS: Computational approaches such as cheminformatic search, virtual screening, pharmacophore modeling, molecular docking and dynamics have been developed and applied to explain the activity of bioactive molecules, design novel agents, increase the success rate of drug research, and decrease the total costs of drug discovery...
July 12, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28704574/unveiling-the-target-promiscuity-of-pharmacologically-active-compounds-in-silico
#14
Petra Schneider, Gisbert Schneider
Drug discovery is governed by the desire to find ligands with defined modes of action. It has been realized that even designated selective drugs may have more macromolecular targets than is commonly thought. Consequently, it will be mandatory to consider multi-target activity for the design of future medicines. Computational models assist medicinal chemists in this effort by helping to eliminate unsuitable lead structures and spot undesired drug effects early in the discovery process. Here, we present a straightforward computational method to find previously unknown targets of pharmacologically active compounds...
July 13, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28704128/commune-health-workers-methadone-maintenance-treatment-mmt-knowledge-and-perceived-difficulties-providing-decentralized-mmt-services-in-vietnam
#15
Chunqing Lin, Nguyen Anh Tuan, Li Li
BACKGROUND: With the initial establishment of countrywide methadone maintenance therapy (MMT) system, Vietnam is in the process of expanding and decentralizing the MMT program to community-based healthcare settings. OBJECTIVE: The study aimed to measure the MMT-related knowledge and perceived difficulties in treating patient who use drugs (PWUD) among community-based healthcare providers, e.g., commune health workers (CHW), and examine its correlated factors. METHODS: A total of 300 CHW from 60 communes in two provinces of Vietnam completed a survey using Audio Computer-Assisted Self-Interview (ACASI) method...
July 13, 2017: Substance Use & Misuse
https://www.readbyqxmd.com/read/28702645/a-perspective-can-copper-complexes-be-developed-as-a-novel-class-of-therapeutics
#16
Mohamed Wehbe, Ada W Y Leung, Michael J Abrams, Chris Orvig, Marcel B Bally
Although copper-ligand complexes appear to be promising as a new class of therapeutics, other than the family of copper(ii) coordination compounds referred to as casiopeínas these compounds have yet to reach the clinic for human use. The pharmaceutical challenges associated with developing copper-based therapeutics will be presented in this article along with a discussion of the potential for high-throughput chemistry, computer-aided drug design, and nanotechnology to address the development of this important class of drug candidates...
July 12, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28699534/discovery-and-development-of-atp-competitive-mtor-inhibitors-using-computational-approaches
#17
Yao Luo, Ling Wang
The mammalian target of rapamycin (mTOR) is a central controller of cell growth, proliferation, metabolism, and angiogenesis. This protein is an attractive target for new anticancer drug development. Significant progress has been made in hit discovery, lead optimization, drug candidate development and determination of the three-dimensional (3D) structure of mTOR. Computational methods have been applied to accelerate the discovery and development of mTOR inhibitors helping to model the structure of mTOR, screen compound databases, uncover structure-activity relationship (SAR) and optimize the hits, mine the privileged fragments and design focused libraries...
July 10, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28699533/class-a-gpcrs-structure-function-modeling-and-structure-based-ligand-design
#18
Xiaojing Cong, Jérémie Topin, Jérôme Golebiowski
G protein-coupled receptors (GPCRs), especially the class A, are the most heavily investigated drug targets in the pharmaceutical industry. Tremendous efforts have been made by both industry and academia to understand the molecular structure and function of this large family of transmembrane proteins. Our understanding in GPCR activation has evolved from the classical inactive-active two-state model to a complex view of GPCR conformational ensemble associated with multiple interacting partners such as ligands, allosteric modulators, ions and downstream signaling proteins...
July 10, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28698923/sequence-symmetry-analysis-in-pharmacovigilance-and-pharmacoepidemiologic-studies
#19
REVIEW
Edward Chia-Cheng Lai, Nicole Pratt, Cheng-Yang Hsieh, Swu-Jane Lin, Anton Pottegård, Elizabeth E Roughead, Yea-Huei Kao Yang, Jesper Hallas
Sequence symmetry analysis (SSA) is a method for detecting adverse drug events by utilizing computerized claims data. The method has been increasingly used to investigate safety concerns of medications and as a pharmacovigilance tool to identify unsuspected side effects. Validation studies have indicated that SSA has moderate sensitivity and high specificity and has robust performance. In this review we present the conceptual framework of SSA and discuss advantages and potential pitfalls of the method in practice...
July 11, 2017: European Journal of Epidemiology
https://www.readbyqxmd.com/read/28696944/mitoriboscins-mitochondrial-based-therapeutics-targeting-cancer-stem-cells-cscs-bacteria-and-pathogenic-yeast
#20
Bela Ozsvari, Marco Fiorillo, Gloria Bonuccelli, Anna Rita Cappello, Luca Frattaruolo, Federica Sotgia, Rachel Trowbridge, Richard Foster, Michael P Lisanti
The "endo-symbiotic theory of mitochondrial evolution" states that mitochondrial organelles evolved from engulfed aerobic bacteria, after millions of years of symbiosis and adaptation. Here, we have exploited this premise to design new antibiotics and novel anti-cancer therapies, using a convergent approach. First, virtual high-throughput screening (vHTS) and computational chemistry were used to identify novel compounds binding to the 3D structure of the mammalian mitochondrial ribosome. The resulting library of ~880 compounds was then subjected to phenotypic drug screening on human cancer cells, to identify which compounds functionally induce ATP-depletion, which is characteristic of mitochondrial inhibition...
July 7, 2017: Oncotarget
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