keyword
MENU ▼
Read by QxMD icon Read
search

Computational drug design

keyword
https://www.readbyqxmd.com/read/28928941/computational-design-of-molecular-motors-as-nanocircuits-in-leishmaniasis
#1
Dipali Kosey, Shailza Singh
Cutaneous leishmaniasis is the most common form of lesihmaniasis, caused by Leishmania major and is spread by the bite of a sandfly .This species infects the macrophages and dendritic cells Due to multi-drug resistance, there is a need for a new therapeutic technique. Recently, a novel molecular motor of Leishmania, Myosin XXI, was classified and characterized. In addition, the drug resistance in this organism has been linked with the overexpression of ABC transporters. Systems biology aims to study the simulation and modeling of natural biological systems whereas synthetic biology deals with building novel and artificial biological parts and devices  Together they have contributed enormously to drug discovery, vaccine design and development, infectious disease detection and diagnostics...
2017: F1000Research
https://www.readbyqxmd.com/read/28927638/quantitative-risk-assessment-via-uncertainty-analysis-in-combination-with-error-propagation-for-the-determination-of-the-dynamic-design-space-of-the-primary-drying-step-during-freeze-drying
#2
Pieter-Jan Van Bockstal, Séverine Thérèse F C Mortier, Jos Corver, Ingmar Nopens, Krist V Gernaey, Thomas De Beer
Traditional pharmaceutical freeze-drying is an inefficient batch process often applied to improve the stability of biopharmaceutical drug products. The freeze-drying process is regulated by the (dynamic) settings of the adaptable process parameters shelf temperature Ts and chamber pressure Pc. Mechanistic modelling of the primary drying step allows the computation of the optimal combination of Ts and Pc in function of the primary drying time. In this study, an uncertainty analysis was performed on the mechanistic primary drying model to construct the dynamic Design Space for the primary drying step of a freeze-drying process, allowing to quantitatively estimate and control the risk of cake collapse (i...
September 16, 2017: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/28927275/proton-coupled-conformational-allostery-modulates-the-inhibitor-selectivity-for-%C3%AE-secretase
#3
Robert C Harris, Cheng-Chieh Tsai, Christopher R Ellis, Jana Shen
Many important pharmaceutical targets, such as aspartyl proteases and kinases, exhibit pH-dependent dynamics, functions and inhibition. Accurate prediction of their binding free energies is challenging because current computational techniques neglect the effects of pH. Here we combine free energy perturbation calculations with continuous constant pH molecular dynamics to explore the selectivity of a small-molecule inhibitor for β-secretase (BACE1), an important drug target for Alzheimer's disease. The calculations predicted identical affinity for BACE1 and the closely-related cathepsin D at high pH; however, at pH 4...
September 19, 2017: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/28925075/understanding-the-catalytic-mechanism-and-the-nature-of-transition-state-of-an-attractive-drug-target-enzyme-shikimate-kinase-by-qm-mm-studies
#4
Jianzhuang Yao, Xia Wang, Haixia Luo, Pengfei Gu
Shikimate kinase (SK), is the fifth bacterial enzyme involved in the shikimate pathway for biosynthesis of life indispensable components, such as aromatic amino acids. Absence of shikimate pathway in human makes SK an attractive target for rational design of drug toward pathogenesis bacteria, such as Mycobacterium tuberculosis and Helicobacter pylori. However, effective inhibitor of SK (e.g., transition state analogue) is still not available in the market due to (at least partly) the lack of knowledge on the catalytic mechanism and the nature of the rate-limiting transition state...
September 18, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28923239/a-novel-formulation-of-inhaled-sodium-cromoglicate-pa101-in-idiopathic-pulmonary-fibrosis-and-chronic-cough-a-randomised-double-blind-proof-of-concept-phase-2-trial
#5
Surinder S Birring, Marlies S Wijsenbeek, Sanjay Agrawal, Jan W K van den Berg, Helen Stone, Toby M Maher, Ahmet Tutuncu, Alyn H Morice
BACKGROUND: Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied...
September 8, 2017: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/28919707/quantum-mechanics-implementation-in-drug-design-workflows-does-it-really-help
#6
REVIEW
Olayide A Arodola, Mahmoud Es Soliman
The pharmaceutical industry is progressively operating in an era where development costs are constantly under pressure, higher percentages of drugs are demanded, and the drug-discovery process is a trial-and-error run. The profit that flows in with the discovery of new drugs has always been the motivation for the industry to keep up the pace and keep abreast with the endless demand for medicines. The process of finding a molecule that binds to the target protein using in silico tools has made computational chemistry a valuable tool in drug discovery in both academic research and pharmaceutical industry...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28916961/practical-computational-toolkits-for-dendrimers-and-dendrons-structure-design
#7
Nuno Martinho, Liana C Silva, Helena F Florindo, Steve Brocchini, Teresa Barata, Mire Zloh
Dendrimers and dendrons offer an excellent platform for developing novel drug delivery systems and medicines. The rational design and further development of these repetitively branched systems are restricted by difficulties in scalable synthesis and structural determination, which can be overcome by judicious use of molecular modelling and molecular simulations. A major difficulty to utilise in silico studies to design dendrimers lies in the laborious generation of their structures. Current modelling tools utilise automated assembly of simpler dendrimers or the inefficient manual assembly of monomer precursors to generate more complicated dendrimer structures...
September 15, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28913743/predicting-the-affinity-of-farnesoid-x-receptor-ligands-through-a-hierarchical-ranking-protocol-a-d3r-grand-challenge-2-case-study
#8
Manon Réau, Florent Langenfeld, Jean-François Zagury, Matthieu Montes
The Drug Design Data Resource (D3R) Grand Challenges are blind contests organized to assess the state-of-the-art methods accuracy in predicting binding modes and relative binding free energies of experimentally validated ligands for a given target. The second stage of the D3R Grand Challenge 2 (GC2) was focused on ranking 102 compounds according to their predicted affinity for Farnesoid X Receptor. In this task, our workflow was ranked 5th out of the 77 submissions in the structure-based category. Our strategy consisted in (1) a combination of molecular docking using AutoDock 4...
September 14, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28912448/a-general-reaction-mechanism-for-carbapenem-hydrolysis-by-mononuclear-and-binuclear-metallo-%C3%AE-lactamases
#9
María-Natalia Lisa, Antonela R Palacios, Mahesh Aitha, Mariano M González, Diego M Moreno, Michael W Crowder, Robert A Bonomo, James Spencer, David L Tierney, Leticia I Llarrull, Alejandro J Vila
Carbapenem-resistant Enterobacteriaceae threaten human health, since carbapenems are last resort drugs for infections by such organisms. Metallo-β-lactamases (MβLs) are the main mechanism of resistance against carbapenems. Clinically approved inhibitors of MBLs are currently unavailable as design has been limited by the incomplete knowledge of their mechanism. Here, we report a biochemical and biophysical study of carbapenem hydrolysis by the B1 enzymes NDM-1 and BcII in the bi-Zn(II) form, the mono-Zn(II) B2 Sfh-I and the mono-Zn(II) B3 GOB-18...
September 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/28911822/structural-insights-of-cyclin-dependent-kinases-implications-in-design-of-selective-inhibitors
#10
REVIEW
Sourav Kalra, Gaurav Joshi, Anjana Munshi, Raj Kumar
There are around 20 Cyclin-dependent kinases (CDKs) known till date, and various research groups have reported their role in different types of cancer. The X-ray structures of some CDKs especially CDK2 was exploited in the past few years, and several inhibitors have been found, e.g., flavopiridol, indirubicin, roscovitine, etc., but due to the specificity issues of these inhibitors (binding to all CDKs), these were called as pan inhibitors. The revolutionary outcome of palbociclib in 2015 as CDK4/6 inhibitor added a new charm to the specific inhibitor design for CDKs...
September 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28911299/in-silico-models-for-nanomedicine-recent-developments
#11
Pietro Mascheroni, Bernhard Aribo Schrefler
Nanomedicine is a recent promising setting for the advancement of current medical therapies, in particular for cancer. Nanoparticle-mediated therapies are aimed to tackle extremely complex phenomena, involving different biochemical, mechanical and biophysical factors. Computational models can contribute to medical research by helping the understanding of biological mechanisms and by providing quantitative analyses. In this work, we report on computational models that address four main issues related to the use of nanoparticles in anti-cancer therapies, namely the delivery of nanoparticles, their uptake by cells, the release of drugs from nano-platforms and nanoparticle-based therapeutics...
April 17, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28899099/accurately-modeling-the-conformational-preferences-of-nucleosides
#12
Mihai Burai Patrascu, Elise Malek-Adamian, Masad J Damha, Nicolas Moitessier
Sugar puckering of nucleosides impacts nucleic acid structures, and hence their biological function. Similarly, nucleoside en-zyme inhibitors may adopt different conformations affecting their binding affinity, DNA incorporation and excision rates. As a result, significant efforts have been made to develop nucleo-side analogues adopting specific conformations to improve bioactivity and pharmacokinetic profiles of the corresponding nucleoside-containing drugs. Understanding and ultimately predicting these conformational preferences would significantly help the design of more effective structures...
September 13, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28892296/tailored-approaches-in-drug-development-and-diagnostics-from-molecular-design-to-biological-model-systems
#13
REVIEW
Cecilia Sahlgren, Annika Meinander, Hongbo Zhang, Fang Cheng, Maren Preis, Chunlin Xu, Tiina A Salminen, Diana Toivola, Daniel Abankwa, Ari Rosling, Didem Şen Karaman, Outi M H Salo-Ahen, Ronald Österbacka, John E Eriksson, Stefan Willför, Ion Petre, Jouko Peltonen, Reko Leino, Mark Johnson, Jessica Rosenholm, Niklas Sandler
Approaches to increase the efficiency in developing drugs and diagnostics tools, including new drug delivery and diagnostic technologies, are needed for improved diagnosis and treatment of major diseases and health problems such as cancer, inflammatory diseases, chronic wounds, and antibiotic resistance. Development within several areas of research ranging from computational sciences, material sciences, bioengineering to biomedical sciences and bioimaging is needed to realize innovative drug development and diagnostic (DDD) approaches...
September 11, 2017: Advanced Healthcare Materials
https://www.readbyqxmd.com/read/28889766/stabilized-helical-peptides-overview-of-the-technologies-and-its-impact-on-drug-discovery
#14
Mark Klein
Protein-protein interactions are predominant in the workings of all cells. Until now, there have been a few successes in targeting protein-protein interactions with small molecules. Peptides may overcome some of the challenges of small molecules in disrupting protein-protein interactions. However, peptides present a new set of challenges in drug discovery. Thus, the study of the stabilization of helical peptides has been extensive. Areas covered: Several technological approaches to helical peptide stabilization have been studied...
September 9, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28889350/binding-free-energy-predictions-of-farnesoid-x-receptor-fxr-agonists-using-a-linear-interaction-energy-lie-approach-with-reliability-estimation-application-to-the-d3r-grand-challenge-2
#15
Eko Aditya Rifai, Marc van Dijk, Nico P E Vermeulen, Daan P Geerke
Computational protein binding affinity prediction can play an important role in drug research but performing efficient and accurate binding free energy calculations is still challenging. In the context of phase 2 of the Drug Design Data Resource (D3R) Grand Challenge 2 we used our automated eTOX ALLIES approach to apply the (iterative) linear interaction energy (LIE) method and we evaluated its performance in predicting binding affinities for farnesoid X receptor (FXR) agonists. Efficiency was obtained by our pre-calibrated LIE models and molecular dynamics (MD) simulations at the nanosecond scale, while predictive accuracy was obtained for a small subset of compounds...
September 9, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28884769/an-experimental-and-computational-framework-for-engineering-multifunctional-nanoparticles-designing-selective-anticancer-therapies
#16
A Aires, J F Cadenas, R Guantes, A L Cortajarena
A key challenge in the treatment of cancer with nanomedicine is to engineer and select nanoparticle formulations that lead to the desired selectivity between tumorigenic and non-tumorigenic cells. To this aim, novel designed nanomaterials, deep biochemical understanding of the mechanisms of interaction between nanomaterials and cells, and computational models are emerging as very useful tools to guide the design of efficient and selective nanotherapies. This works shows, using a combination of detailed experimental approaches and simulations, that the specific targeting of cancer cells in comparison to non-tumorigenic cells can be achieved through the custom design of multivalent nanoparticles...
September 8, 2017: Nanoscale
https://www.readbyqxmd.com/read/28884249/cdocker-and-formula-see-text-dynamics-for-prospective-prediction-in-d3r-grand-challenge-2
#17
Xinqiang Ding, Ryan L Hayes, Jonah Z Vilseck, Murchtricia K Charles, Charles L Brooks
The opportunity to prospectively predict ligand bound poses and free energies of binding to the Farnesoid X Receptor in the D3R Grand Challenge 2 provided a useful exercise to evaluate CHARMM based docking (CDOCKER) and [Formula: see text]-dynamics methodologies for use in "real-world" applications in computer aided drug design. In addition to measuring their current performance, several recent methodological developments have been analyzed retrospectively to highlight best procedural practices in future applications...
September 7, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28881961/rectified-factor-networks-for-biclustering-of-omics-data
#18
Djork-Arné Clevert, Thomas Unterthiner, Gundula Povysil, Sepp Hochreiter
Motivation: Biclustering has become a major tool for analyzing large datasets given as matrix of samples times features and has been successfully applied in life sciences and e-commerce for drug design and recommender systems, respectively. actor nalysis for cluster cquisition (FABIA), one of the most successful biclustering methods, is a generative model that represents each bicluster by two sparse membership vectors: one for the samples and one for the features. However, FABIA is restricted to about 20 code units because of the high computational complexity of computing the posterior...
July 15, 2017: Bioinformatics
https://www.readbyqxmd.com/read/28881288/hydroxytriazole-derivatives-as-potent-and-selective-aldo-keto-reductase-1c3-akr1c3-inhibitors-discovered-by-bioisosteric-scaffold-hopping-approach
#19
Agnese C Pippione, Alessandro Giraudo, Davide Bonanni, Irene M Carnovale, Elisabetta Marini, Clara Cena, Annalisa Costale, Daniele Zonari, Klaus Pors, Maria Sadiq, Donatella Boschi, Simonetta Oliaro-Bosso, Marco L Lolli
The aldo-keto reductase 1C3 isoform (AKR1C3) plays a vital role in the biosynthesis of androgens, making this enzyme an attractive target for castration-resistant prostate cancer therapy. Although AKR1C3 is a promising drug target, no AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid, a non-steroidal anti-inflammatory drug, is known to potently inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. To diminish off-target effects, we have applied a scaffold hopping strategy replacing the benzoic acid moiety of flufenamic acid with an acidic hydroxyazolecarbonylic scaffold...
August 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28881183/from-machine-learning-to-deep-learning-progress-in-machine-intelligence-for-rational-drug-discovery
#20
REVIEW
Lu Zhang, Jianjun Tan, Dan Han, Hao Zhu
Machine intelligence, which is normally presented as artificial intelligence, refers to the intelligence exhibited by computers. In the history of rational drug discovery, various machine intelligence approaches have been applied to guide traditional experiments, which are expensive and time-consuming. Over the past several decades, machine-learning tools, such as quantitative structure-activity relationship (QSAR) modeling, were developed that can identify potential biological active molecules from millions of candidate compounds quickly and cheaply...
September 4, 2017: Drug Discovery Today
keyword
keyword
84853
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"