keyword
MENU ▼
Read by QxMD icon Read
search

Computational drug design

keyword
https://www.readbyqxmd.com/read/29352161/the-action-of-a-negative-allosteric-modulator-at-the-dopamine-d2-receptor-is-dependent-upon-sodium-ions
#1
Christopher J Draper-Joyce, Ravi Kumar Verma, Mayako Michino, Jeremy Shonberg, Anitha Kopinathan, Carmen Klein Herenbrink, Peter J Scammells, Ben Capuano, Ara M Abramyan, David M Thal, Jonathan A Javitch, Arthur Christopoulos, Lei Shi, J Robert Lane
Sodium ions (Na+) allosterically modulate the binding of orthosteric agonists and antagonists to many class A G protein-coupled receptors, including the dopamine D2 receptor (D2R). Experimental and computational evidences have revealed that this effect is mediated by the binding of Na+ to a conserved site located beneath the orthosteric binding site (OBS). SB269652 acts as a negative allosteric modulator (NAM) of the D2R that adopts an extended bitopic pose, in which the tetrahydroisoquinoline moiety interacts with the OBS and the indole-2-carboxamide moiety occupies a secondary binding pocket (SBP)...
January 19, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29351374/fast-dynamic-docking-guided-by-adaptive-electrostatic-bias-the-md-binding-approach
#2
Andrea Spitaleri, Sergio Decherchi, Andrea Cavalli, Walter Rocchia
Engineering chemical entities to modify how pharmaceutical targets function, as it is done in drug design, requires a good understanding of molecular recognition and binding. In this context, the limitations of statically describing bimolecular recognition, as done in docking/scoring, call for insightful and efficient dynamical investigations. On the experimental side, the characterization of dynamical binding processes is still in its infancy. Thus, computer simulations, particularly molecular dynamics (MD), are compelled to play a prominent role, allowing a deeper comprehension of the binding process and its causes and thus a more informed compound selection, making more significant the computational contribution to drug discovery1...
January 19, 2018: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/29349918/dual-drug-backboned-shattering-polymeric-theranostic-nanomedicine-for-synergistic-eradication-of-patient-derived-lung-cancer
#3
Yuwei Cong, Haihua Xiao, Hejian Xiong, Zigui Wang, Jianxun Ding, Chan Li, Xuesi Chen, Xing-Jie Liang, Dongfang Zhou, Yubin Huang
Most of the current nanoparticle-based therapeutics worldwide failing in clinical trials face three major challenges: (i) lack of an optimum drug delivery platform with precise composition, (ii) lack of a method of directly monitoring the fate of a specific drug rather than using any other labelling molecules as a compromise, and (iii) lack of reliable cancer models with high fidelity for drug screen and evaluation. Here, starting from a PP2A inhibitor demethylcantharidin (DMC) and cisplatin, the design of a dual sensitive dual drug backboned shattering polymer (DDBSP) with exact composition at a fixed DMC/Pt ratio for precise nanomedicine is shown...
January 19, 2018: Advanced Materials
https://www.readbyqxmd.com/read/29349448/a-study-on-platinum-iv-species-containing-an-estrogen-receptor-modulator-to-reverse-tamoxifen-resistance-of-breast-cancer
#4
Weiwei Hu, Jian Zhao, Wuyang Hua, Shaohua Gou
Several dual-action Tam-Pt(iv) complexes derived from tamoxifen (Tam) and platinum(ii) drugs were designed and synthesized for targeting estrogen receptors (ERs) and DNA. These novel compounds not only exhibited potent cytotoxicity against breast cancer cells, but also reversed the tamoxifen resistance of TamR-MCF-7 cancer cells. Computational docking assays together with cellular uptake data demonstrated that the ER ligand portion of these conjugates plays a targeting role in ER-positive tumor cells and promotes the uptake of platinum via an estrogen receptor-mediated pathway...
January 19, 2018: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/29348235/digitization-of-multistep-organic-synthesis-in-reactionware-for-on-demand-pharmaceuticals
#5
Philip J Kitson, Guillaume Marie, Jean-Patrick Francoia, Sergey S Zalesskiy, Ralph C Sigerson, Jennifer S Mathieson, Leroy Cronin
Chemical manufacturing is often done at large facilities that require a sizable capital investment and then produce key compounds for a finite period. We present an approach to the manufacturing of fine chemicals and pharmaceuticals in a self-contained plastic reactionware device. The device was designed and constructed by using a chemical to computer-automated design (ChemCAD) approach that enables the translation of traditional bench-scale synthesis into a platform-independent digital code. This in turn guides production of a three-dimensional printed device that encloses the entire synthetic route internally via simple operations...
January 19, 2018: Science
https://www.readbyqxmd.com/read/29345580/multi-potent-natural-scaffolds-targeting-amyloid-cascade-in-search-of-alzheimer-s-disease-therapeutics
#6
Sandipan Chakraborty
Alzheimer's disease (AD) once considered a rare disorder emerges as a major health concern in recent times. The disease pathogenesis is very complex and yet to be understood completely. However, "Amyloid Cascade" is the central event in disease pathogenesis. Several proteins of the amyloid cascade are currently being considered as potential targets for AD therapeutics discovery. Many potential compounds are in clinical trials, but till now there is no known cure for the disease. Recent years have witnessed remarkable research interest in search of novel concepts in drug designing for AD...
January 16, 2018: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/29344898/methods-for-high-throughput-drug-combination-screening-and-synergy-scoring
#7
Liye He, Evgeny Kulesskiy, Jani Saarela, Laura Turunen, Krister Wennerberg, Tero Aittokallio, Jing Tang
Gene products or pathways that are aberrantly activated in cancer but not in normal tissue hold great promises for being effective and safe anticancer therapeutic targets. Many targeted drugs have entered clinical trials but so far showed limited efficacy mostly due to variability in treatment responses and often rapidly emerging resistance. Toward more effective treatment options, we will need multi-targeted drugs or drug combinations, which selectively inhibit the viability and growth of cancer cells and block distinct escape mechanisms for the cells to become resistant...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29343185/exploring-protein-protein-intermolecular-recognition-between-meprin-%C3%AE-and-endogenous-protease-regulator-cystatinc-coupled-with-pharmacophore-elucidation
#8
Ankur Chaudhuri, Sampa Biswas, Sibani Chakraborty
Meprins are a group of zinc metalloproteases of the astacin family which play pivotal role in several physiological and pathologocal diseases. The inhibition of the meprins by various inhibitors; macromolecular and small molecules are crucial in the control of several diseases. Human cystatinC, an amyloidogenic protein is reported to be an endogenous inhibitor of meprin-α. In this computational study, we elucidate a rational model for meprinα-cystatinC complex by using protein-protein docking. The complex model as well as the unbound form was evaluated by molecular dynamics simulation...
January 17, 2018: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29341913/characterisation-of-pore-structures-of-pharmaceutical-tablets-a-review
#9
REVIEW
Daniel Markl, Alexa Strobel, Rüdiger Schlossnikl, Johan Bøtker, Prince Bawuah, Cathy Ridgway, Jukka Rantanen, Thomas Rades, Patrick Gane, Kai-Erik Peiponen, J Axel Zeitler
Traditionally, the development of a new solid dosage form is formulation-driven and less focus is put on the design of a specific microstructure for the drug delivery system. However, the compaction process particularly impacts the microstructure, or more precisely, the pore architecture in a pharmaceutical tablet. Besides the formulation, the pore structure is a major contributor to the overall performance of oral solid dosage forms as it directly affects the liquid uptake rate, which is the very first step of the dissolution process...
January 13, 2018: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/29340951/a-perspective-on-multi-target-drug-discovery-and-design-for-complex-diseases
#10
Rona R Ramsay, Marija R Popovic-Nikolic, Katarina Nikolic, Elisa Uliassi, Maria Laura Bolognesi
Diseases of infection, of neurodegeneration (such as Alzheimer's and Parkinson's diseases), and of malignancy (cancers) have complex and varied causative factors. Modern drug discovery has the power to identify potential modulators for multiple targets from millions of compounds. Computational approaches allow the determination of the association of each compound with its target before chemical synthesis and biological testing is done. These approaches depend on the prior identification of clinically and biologically validated targets...
January 17, 2018: Clinical and Translational Medicine
https://www.readbyqxmd.com/read/29339792/assemble-and-match-a-novel-hybrid-tool-for-enhancing-education-and-research-in-rational-structure-based-drug-design
#11
Pouya Tavousi, Reza Amin, Sina Shahbazmohamadi
Rational drug design is the process of finding new medication that can activate or inhibit the biofunction of a target molecule by binding to it and forming a molecular complex. Here, shape and charge complementarities between drug and target are key. To help find effective drug molecules out of a huge pool of possibilities, physical and computer aided tools have been developed. Former offers a tangible experience of the molecular interactions yet lacks measurement and evaluation capabilities. Latter enables accurate and fast evaluations, but does not deliver the interactive tangible experience of physical models...
January 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29339082/water-mediated-interactions-enable-smooth-substrate-transport-in-a-bacterial-efflux-pump
#12
Attilio Vittorio Vargiu, Venkata Krishnan Ramaswamy, Ivana Malvacio, Giuliano Malloci, Ulrich Kleinekathöfer, Paolo Ruggerone
BACKGROUND: Efflux pumps of the Resistance-Nodulation-cell Division superfamily confer multi-drug resistance to Gram-negative bacteria. The most-studied polyspecific transporter belonging to this class is the inner-membrane trimeric antiporter AcrB of Escherichia coli. In previous studies, a functional rotation mechanism was proposed for its functioning, according to which the three monomers undergo concerted conformational changes facilitating the extrusion of substrates. However, the molecular determinants and the energetics of this mechanism still remain unknown, so its feasibility must be proven mechanistically...
January 12, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29337562/physiologically-based-pharmacokinetic-modeling-in-lead-optimization-ii-rational-bioavailability-design-by-global-sensitivity-analysis-to-identify-properties-affecting-bioavailability
#13
Pankaj R Daga, Michael B Bolger, Ian Haworth, Robert Daniel Clark, Eric J Martin
When medicinal chemists need to improve oral bioavailability (%F) during lead optimization, they systematically modify compound properties mainly based on their own experience and general rules of thumb. However, at least a dozen properties can influence %F, and the difficulty of multi-parameter optimization for such complex non-linear processes grows combinatorially with the number of variables. Furthermore, strategies can be in conflict. For example, adding a polar or charged group will generally increase solubility but decrease permeability...
January 16, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29337438/3d-e-chem-structural-cheminformatics-workflows-for-computer-aided-drug-discovery
#14
Albert J Kooistra, Marton Vass, Ross McGuire, Rob Leurs, Iwan Jp de Esch, Gerrit Vriend, Stefan Verhoeven, Chris de Graaf
eScience technologies are needed to process the information available in many heterogeneous types of protein-ligand interaction data and to capture these data into models that enable the design of efficacious and safe medicines. Here we present scientific KNIME tools and workflows that enable the integration of chemical, pharmacological, and structural information for: i) structure-based bioactivity data mapping, ii) structure-based identification of scaffold replacement strategies for ligand design, iii) ligand-based target prediction, iv) protein sequence-based binding site identification and ligand repurposing, and v) structure-based pharmacophore comparison for ligand repurposing across protein families...
January 16, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29336266/design-synthesis-evaluation-and-computational-studies-of-nipecotic-acid-acetonaphthone-hybrids-as-potential-antiepileptic-agents
#15
Ankit Seth, Piyoosh A Sharma, Avanish Tripathi, Priyanka K Choubey, Pavan Srivastava, Prabhash N Tripathi, Sushant Kumar Shrivastava
BACKGROUND: Nipecotic acid is considered to be one of the most potent inhibitors of neuronal and glial γ- aminobutyric acid (GABA) uptake in vitro. However nipecotic acid does not readily cross the blood-brain barrier (BBB) following peripheral administration, owing to its hydrophilic nature. OBJECTIVE: A series of substituted acetonaphthones tethered nipecotic acid derivatives were designed and synthesized with an aim to improve the lipophilicity and the blood-brain barrier (BBB) permeation...
January 15, 2018: Medicinal Chemistry
https://www.readbyqxmd.com/read/29331129/perspective-structural-fluctuation-of-protein-and-anfinsen-s-thermodynamic-hypothesis
#16
Fumio Hirata, Masatake Sugita, Masasuke Yoshida, Kazuyuki Akasaka
The thermodynamics hypothesis, casually referred to as "Anfinsen's dogma," is described theoretically in terms of a concept of the structural fluctuation of protein or the first moment (average structure) and the second moment (variance and covariance) of the structural distribution. The new theoretical concept views the unfolding and refolding processes of protein as a shift of the structural distribution induced by a thermodynamic perturbation, with the variance-covariance matrix varying. Based on the theoretical concept, a method to characterize the mechanism of folding (or unfolding) is proposed...
January 14, 2018: Journal of Chemical Physics
https://www.readbyqxmd.com/read/29330125/the-hitchhiker-s-guide-to-the-chemical-biological-galaxy
#17
REVIEW
Giulia Opassi, Alessandro Gesù, Alberto Massarotti
We are used to considering chemical and biological spaces as two different entities; although they represent a more-interconnected world, in fact they represent a Yin-Yang concept in drug discovery. Chemical-biological space is as vast as the universe and, as Douglas Adams famously said, 'Space is big. You just won't believe how vastly, hugely, mind-bogglingly big it is'. However, many researchers are convinced that it is not so infinite, and are designing computational and experimental tools to help identify and explore all possible chemical-biological space...
January 9, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29329551/efficacy-and-safety-of-combined-treatment-of-miniscalpel-acupuncture-and-non-steroidal-anti-inflammatory-drugs-an-assessor-blinded-randomized-controlled-pilot-study
#18
Seungah Jun, Jung Hee Lee, Han Mi Gong, Yeon-Joong Chung, Ju-Ran Kim, Chung A Park, Seong Hun Choi, Geon-Mok Lee, Hyun-Jong Lee, Jae Soo Kim
BACKGROUND: Chronic neck pain is a common musculoskeletal disease during the lifespan of an individual. With an increase in dependence on computer technology, the prevalence of chronic neck pain is expected to rise and this can lead to socioeconomic problems. We have designed the current pilot study to evaluate the efficacy and safety of miniscalpel acupuncture treatment combined with non-steroidal anti-inflammatory drugs (NSAIDs) in patients with chronic neck pain. METHODS: This seven-week clinical trial has been designed as an assessor-blinded, randomized controlled trial with three parallel arms...
January 12, 2018: Trials
https://www.readbyqxmd.com/read/29329283/modeling-the-assembly-order-of-multimeric-heteroprotein-complexes
#19
Lenna X Peterson, Yoichiro Togawa, Juan Esquivel-Rodriguez, Genki Terashi, Charles Christoffer, Amitava Roy, Woong-Hee Shin, Daisuke Kihara
Protein-protein interactions are the cornerstone of numerous biological processes. Although an increasing number of protein complex structures have been determined using experimental methods, relatively fewer studies have been performed to determine the assembly order of complexes. In addition to the insights into the molecular mechanisms of biological function provided by the structure of a complex, knowing the assembly order is important for understanding the process of complex formation. Assembly order is also practically useful for constructing subcomplexes as a step toward solving the entire complex experimentally, designing artificial protein complexes, and developing drugs that interrupt a critical step in the complex assembly...
January 12, 2018: PLoS Computational Biology
https://www.readbyqxmd.com/read/29328649/phenylthiomethyl-ketone-based-fragments-show-selective-and-irreversible-inhibition-of-enteroviral-3c-proteases
#20
Robert Schulz, Amira Atef, Daniel Becker, Franziska Gottschalk, Carolin Tauber, Stefan Wagner, Christoph Arkona, Atef A Abdel-Hafez, Hassan H Farag, Jörg Rademann, Gerhard Wolber
Lead structure discovery mainly focuses on the identification of noncovalently binding ligands. Covalent linkage, however, is an essential binding mechanism for a multitude of successfully marketed drugs although discovered by serendipity in most cases. We present a concept for the design of fragments covalently binding to proteases. Covalent linkage enables fragment binding unrelated to affinity to shallow protein binding sites and at the same time allows differentiated targeted hit verification and binding location verification through mass spectrometry...
January 12, 2018: Journal of Medicinal Chemistry
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"