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Computational drug design

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https://www.readbyqxmd.com/read/29789564/establishing-quasi-steady-state-operations-of-microphysiological-systems-mps-using-tissue-specific-metabolic-dependencies
#1
Christian Maass, Matthew Dallas, Matthew E LaBarge, Michael Shockley, Jorge Valdez, Emily Geishecker, Cynthia L Stokes, Linda G Griffith, Murat Cirit
Microphysiological systems (MPS), consisting of tissue constructs, biomaterials, and culture media, aim to recapitulate relevant organ functions in vitro. MPS components are housed in fluidic hardware with operational protocols, such as periodic complete media replacement. Such batch-like operations provide relevant nutrients and remove waste products but also reset cell-secreted mediators (e.g. cytokines, hormones) and potentially limit exposure to drugs (and metabolites). While each component plays an essential role for tissue functionality, MPS-specific nutrient needs are not yet well-characterized nor utilized to operate MPSs at more physiologically-relevant conditions...
May 22, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29789513/substructural-connectivity-fingerprint-and-extreme-entropy-machines-a-new-method-of-compound-representation-and-analysis
#2
Krzysztof Rataj, Wojciech Czarnecki, Sabina Podlewska, Agnieszka Pocha, Andrzej J Bojarski
Key-based substructural fingerprints are an important element of computer-aided drug design techniques. The usefulness of the fingerprints in filtering compound databases is invaluable, as they allow for the quick rejection of molecules with a low probability of being active. However, this method is flawed, as it does not consider the connections between substructures. After changing the connections between particular chemical moieties, the fingerprint representation of the compound remains the same, which leads to difficulties in distinguishing between active and inactive compounds...
May 23, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29788889/targeting-key-transporters-in-tumor-glycolysis-as-a-novel-anticancer-strategy
#3
Yunli Shi, Shengnan Liu, Shabir Ahmad, Qingzhi Gao
Increased glycolysis has been one of the metabolic characteristics known as the Warburg effect. The functional and therapeutic importance of the Warburg effect in targeted therapy is scientifically recognized and the glucose metabolic pathway has become a desirable target of anticancer strategies. Glucose transporters (GLUTs) play an important role in cancer glycolysis to sustain cancer cell proliferation, metastasis and survival. Utilizing the knowledge of differential expression and biological functions of GLUTs offers us the possibility of designing and delivering chemotherapeutics toward targeted tumor tissues for improved cancer selectivity...
May 22, 2018: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/29780994/molecular-mechanism-of-15-lipoxygenase-allosteric-activation-and-inhibition
#4
Hu Meng, Ziwei Dai, Weilin Zhang, Ying Liu, Luhua Lai
Human reticulocyte 15-lipoxygenase (15-LOX) plays an important role in inflammation resolution and is also involved in many cancer-related processes. Both an activator and an inhibitor will serve as research tools for understanding the biological functions of 15-LOX and provide opportunities for drug discovery. In a previous study, both allosteric activators and inhibitors of 15-LOX were discovered through a virtual screening based computational approach. However, why molecules binding to the same site causes different effects remains to be disclosed...
May 21, 2018: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/29780310/mobile-software-as-a-medical-device-samd-for-the-treatment-of-epilepsy-development-of-digital-therapeutics-comprising-behavioral-and-music-based-interventions-for-neurological-disorders
#5
Pegah Afra, Carol S Bruggers, Matthew Sweney, Lilly Fagatele, Fareeha Alavi, Michael Greenwald, Merodean Huntsman, Khanhly Nguyen, Jeremiah K Jones, David Shantz, Grzegorz Bulaj
Digital health technologies for people with epilepsy (PWE) include internet-based resources and mobile apps for seizure management. Since non-pharmacological interventions, such as listening to specific Mozart's compositions, cognitive therapy, psychosocial and educational interventions were shown to reduce epileptic seizures, these modalities can be integrated into mobile software and delivered by mobile medical apps as digital therapeutics. Herein, we describe: (1) a survey study among PWE about preferences to use mobile software for seizure control, (2) a rationale for developing digital therapies for epilepsy, (3) creation of proof-of-concept mobile software intended for use as an adjunct digital therapeutic to reduce seizures, and (4) broader applications of digital therapeutics for the treatment of epilepsy and other chronic disorders...
2018: Frontiers in Human Neuroscience
https://www.readbyqxmd.com/read/29768999/essentials-and-perspectives-of-computational-modelling-assistance-for-cns-oriented-nanoparticle-based-drug-delivery-systems
#6
Joanna Kisała, Kinga I Heclik, Krzysztof Pogocki, Dariusz Pogocki
The blood-brain barrier (BBB) is a complex system controlling two-way substances traffic between circulatory (cardiovascular) system and central nervous system (CNS). It is almost perfectly crafted to regulate brain homeostasis and to permit selective transport of molecules that are essential for brain function. For potential drug candidates, the CNS-oriented neuropharmaceuticals as well as for those of primary targets in the periphery, the extent to which a substance in the circulation gains access to the CNS seems crucial...
May 16, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29762023/reinforced-adversarial-neural-computer-for-de-novo-molecular-design
#7
Evgeny Putin, Arip Asadulaev, Yan Ivanenkov, Vladimir Aladinskiy, Benjamin Sánchez-Lengeling, Alán Aspuru-Guzik, Alex Zhavoronkov
In silico modeling is a crucial milestone in modern drug design & development. Although computer-aided approaches in this field are well-studied, the application of deep learning methods in this research area is at the beginning. In this work, we present an original deep neural network (DNN) architecture named RANC (Reinforced Adversarial Neural Computer) for the de novo design of novel small-molecule organic structures based on generative adversarial network (GAN) paradigm and reinforcement learning (RL)...
May 15, 2018: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29761349/intracochlear-administration-of-steroids-with-a-catheter-during-human-cochlear-implantation-a-safety-and-feasibility-study
#8
Nils K Prenzler, Rolf Salcher, Max Timm, Lutz Gaertner, Thomas Lenarz, Athanasia Warnecke
Suppression of foreign body reaction, improvement of electrode-nerve interaction, and preservation of residual hearing are essential research topics in cochlear implantation. Intracochlear pharmaco- or cell-based therapies can open new horizons in this field. Local drug delivery strategies are desirable as higher local concentrations of agents can be realized and side effects can be minimized compared to systemic administrations. When administered locally at accessible, basal parts of the cochlea, drugs reach apical regions later and in much lower concentrations due to poor diffusion patterns in cochlear fluids...
May 14, 2018: Drug Delivery and Translational Research
https://www.readbyqxmd.com/read/29760101/design-of-an-allosterically-modulated-doxycycline-and-doxorubicin-drug-binding-protein
#9
Karin Schmidt, Bernd R Gardill, Alina Kern, Peter Kirchweger, Michael Börsch, Yves A Muller
The allosteric interplay between distant functional sites present in a single protein provides for one of the most important regulatory mechanisms in biological systems. While the design of ligand-binding sites into proteins remains challenging, this holds even truer for the coupling of a newly engineered binding site to an allosteric mechanism that regulates the ligand affinity. Here it is shown how computational design algorithms enabled the introduction of doxycycline- and doxorubicin-binding sites into the serine proteinase inhibitor (serpin) family member α1-antichymotrypsin...
May 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29756561/advances-in-the-treatment-of-explicit-water-molecules-in-docking-and-binding-free-energy-calculations
#10
Xiao Hu, Irene Maffucci, Alessandro Contini
BACKGROUND: The inclusion of direct effects mediated by water during the ligand-receptor recognition is a hot-topic of modern computational chemistry applied to drug discovery and development. Docking or virtual screening with explicit hydration is still debatable, despite the successful cases that have been presented in the last years. Indeed, how to select the water molecules that will be included in the docking process or how the included waters should be treated remain open questions...
May 13, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29756074/discovery-of-small-molecules-through-pharmacophore-modeling-docking-and-molecular-dynamics-simulation-against-plasmodium-vivax-vivapain-3-vp-3
#11
Madhu Sudhana Saddala, Pradeepkiran Jangampalli Adi
Vivapain-3(VP-3) protein is a family of cysteine rich proteases of malaria parasite is extensively reported to participate in a range of wide cellular processes including survival. VP-3 of plasmodium recognized as an attractive drug target in vector-borne diseases like malaria. In the present study we robust a homology model of VP-3 protein and generated the pharmacophore based models adapted to screen the best drug like compounds from PubChem database. Our results finds the fourteen best lead molecules were mapped with core pharmacophore features of VP-3 and top hits were further evaluated by molecular dynamics simulation and docking studies...
May 2018: Heliyon
https://www.readbyqxmd.com/read/29755970/how-to-achieve-better-results-using-pass-based-virtual-screening-case-study-for-kinase-inhibitors
#12
Pavel V Pogodin, Alexey A Lagunin, Anastasia V Rudik, Dmitry A Filimonov, Dmitry S Druzhilovskiy, Mark C Nicklaus, Vladimir V Poroikov
Discovery of new pharmaceutical substances is currently boosted by the possibility of utilization of the Synthetically Accessible Virtual Inventory (SAVI) library, which includes about 283 million molecules, each annotated with a proposed synthetic one-step route from commercially available starting materials. The SAVI database is well-suited for ligand-based methods of virtual screening to select molecules for experimental testing. In this study, we compare the performance of three approaches for the analysis of structure-activity relationships that differ in their criteria for selecting of "active" and "inactive" compounds included in the training sets...
2018: Frontiers in Chemistry
https://www.readbyqxmd.com/read/29753941/an-integrated-computational-approach-of-molecular-dynamics-simulations-receptor-binding-studies-and-pharmacophore-mapping-analysis-in-search-of-potent-inhibitors-against-tuberculosis
#13
Shivangi Agarwal, Ekta Verma, Vivek Kumar, Namrita Lall, Samaresh Sau, Arun K Iyer, Sushil K Kashaw
Tuberculosis is an infectious chronic disease caused by obligate pathogen Mycobacterium tuberculosis that affects millions of people worldwide. Although many first and second line drugs are available for its treatment, but their irrational use has adversely lead to the emerging cases of multiple drug resistant and extensively drug-resistant tuberculosis. Therefore, there is an intense need to develop novel potent analogues for its treatment. This has prompted us to develop potent analogues against TB. The Mycobacterium tuberculosis genome provides us with number of validated targets to combat against TB...
May 3, 2018: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29746776/from-cancer-to-pain-target-by-automated-selectivity-inversion-of-a-clinical-candidate
#14
Samo Turk, Benjamin Merget, Sameh Eid, Simone Fulle
Elimination of inadvertent binding is crucial for inhibitor design targeting conserved protein classes like kinases. Compounds in clinical trials provide a rich source for initiating drug design efforts by exploiting such secondary binding events. Considering both aspects, we shifted the selectivity of tozasertib, originally developed against AurA as cancer target, towards the pain target TrkA. First, selectivity-determining features in binding pockets were identified by fusing interaction-grids of several key and off-target conformations...
May 10, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29746491/emergence-and-selection-of-isoniazid-and-rifampin-resistance-in-tuberculosis-granulomas
#15
Elsje Pienaar, Jennifer J Linderman, Denise E Kirschner
Drug resistant tuberculosis is increasing world-wide. Resistance against isoniazid (INH), rifampicin (RIF), or both (multi-drug resistant TB, MDR-TB) is of particular concern, since INH and RIF form part of the standard regimen for TB disease. While it is known that suboptimal treatment can lead to resistance, it remains unclear how host immune responses and antibiotic dynamics within granulomas (sites of infection) affect emergence and selection of drug-resistant bacteria. We take a systems pharmacology approach to explore resistance dynamics within granulomas...
2018: PloS One
https://www.readbyqxmd.com/read/29745612/-local-helix-parameters-fitting-of-proteins-based-on-dual-quaternions-registration-method
#16
Yonghong Xu, Shaowei Zhang, Jun Jing, Yong Zhao, Feixiang Hou
A fitting method of calculating local helix parameters of proteins based on dual quaternions registration fitting (DQRFit) is proposed in this paper. First, the C and N atom coordinates of each residue in the protein structure data are extracted. Then the unregistered data and reference data are constructed using the sliding windows. The square sum of the distance of the data points before and after registration is regarded as an optimization goal. We calculate the optimal rotation matrix and the translation vector using the dual quaternion registration algorithm, and get the helix parameters of the secondary structure which contain the number of residues per turn( τ ), helix radius( ρ )and helix pitch( p )...
February 1, 2018: Sheng Wu Yi Xue Gong Cheng Xue za Zhi, Journal of Biomedical Engineering, Shengwu Yixue Gongchengxue Zazhi
https://www.readbyqxmd.com/read/29741393/molecular-docking-of-immunogenic-peptide-of-toxoplasma-gondii-and-encapsulation-with-polymer-as-vaccine-candidate
#17
Rabia Cakir-Koc, Yasemin Budama-Kilinc, Yagmur Kokcu, Serda Kecel-Gunduz
Toxoplasma gondii is one of the most widely spread parasitic organisms in the world. T. gondii causes primary, chronic infection and mortality. Major surface antigen 1 is the most abundant tachyzoite surface protein and highly conserved between species and causes strong humoural response. Some studies showed that the peptide sequence of surface antigen has immunity. Therefore, tachyzoite surface antigenic peptide sequence is one of the good candidates for vaccine development. However, conformational information and delivery systems are very important parameters for vaccine development...
May 9, 2018: Artificial Cells, Nanomedicine, and Biotechnology
https://www.readbyqxmd.com/read/29741140/modern-approaches-for-the-discovery-of-anti-infectious-drugs-for-the-treatment-of-neglected-diseases
#18
Carolina L Bellera, Maria L Sbaraglini, Alan Talevi
Neglected diseases comprise a number of infectious diseases historically endemic to low- and middle-income countries, though recently they have spread to high-income countries due to human migrations. In the past, pharmaceutical companies have shown hesitant to invest in these health conditions, due to the limited return on investment. As a result, the role of the academic sector and non-for-profit organizations in the discovery of new drugs for neglected diseases has been particularly relevant. <p> Here, we review recent applications of modern drug discovery technologies in the field of neglected diseases, including high-throughput screening, in silico screening and computer-aided drug design...
May 9, 2018: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/29739852/a-computational-approach-for-predicting-off-target-toxicity-of-antiviral-ribonucleoside-analogues-to-mitochondrial-rna-polymerase
#19
Holly Freedman, Philip Winter, Jack Tuszynski, D Lorne Tyrrell, Michael Houghton
In the development of antiviral drugs that target viral RNA-dependent RNA polymerases, off-target toxicity due to the inhibition of the human mitochondrial RNA polymerase (POLRMT) is a major liability. Therefore, it is essential that all new ribonucleoside analogue drugs be accurately screened for POLRMT inhibition. A computational tool that can accurately predict NTP binding to POLRMT could assist in evaluating any potential toxicity, and in designing possible salvaging strategies. Using the available crystal structure of POLRMT bound to an RNA transcript, here we created a model of POLRMT with an NTP molecule bound in the active site...
May 8, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29738823/when-fragments-link-a-bibliometric-perspective-on-the-development-of-fragment-based-drug-discovery
#20
REVIEW
Angelo K S Romasanta, Peter van der Sijde, Iina Hellsten, Roderick E Hubbard, Gyorgy M Keseru, Jacqueline van Muijlwijk-Koezen, Iwan J P de Esch
Fragment-based drug discovery (FBDD) is a highly interdisciplinary field, rich in ideas integrated from pharmaceutical sciences, chemistry, biology, and physics, among others. To enrich our understanding of the development of the field, we used bibliometric techniques to analyze 3642 publications in FBDD, complementing accounts by key practitioners. Mapping its core papers, we found the transfer of knowledge from academia to industry. Co-authorship analysis showed that university-industry collaboration has grown over time...
May 5, 2018: Drug Discovery Today
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