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RANK ligand

Noriaki Okimoto, Atsushi Suenaga, Makoto Taiji
In computational drug design, ranking a series of compound analogues in a manner that is consistent with experimental affinities remains a challenge. In this study, we evaluated the prediction of protein-ligand binding affinities using steered molecular dynamics simulations. First, we investigated the appropriate conditions for accurate predictions in these simulations. A conic harmonic restraint was applied to the system for efficient sampling of work values on the ligand unbinding pathway. We found that pulling velocity significantly influenced affinity predictions, but that the number of collectable trajectories was less influential...
October 24, 2016: Journal of Biomolecular Structure & Dynamics
Dimitrios Spiliotopoulos, Amedeo Caflisch
We review the results of fragment-based high-throughput docking to the N-terminal bromodomain of BRD4 and the CREBBP bromodomain. In both docking campaigns the ALTA (anchor-based library tailoring) procedure was used to reduce the size of the initial library by selecting for flexible docking only the molecules that contain a fragment with favorable predicted binding energy. Ranking by a force field-based energy with solvation has resulted in small-molecule hits with low-micromolar affinity and favorable ligand efficiency...
March 2016: Drug Discovery Today. Technologies
Sajjad Karim, Jaudah A Al-Maghrabi, Hasan M A Farsi, Ahmad J Al-Sayyad, Hans-Juergen Schulten, Abdelbaset Buhmeida, Zeenat Mirza, Alaa A Al-Boogmi, Fai T Ashgan, Manal M Shabaad, Hend F NourEldin, Khalid B M Al-Ghamdi, Adel Abuzenadah, Adeel G A Chaudhary, Mohammed H Al-Qahtani
BACKGROUND: Renal cell carcinoma (RCC) is a seventh ranked malignancy with poor prognosis. RCC is lethal at metastatic stage as it does not respond to conventional systemic treatments, and there is an urgent need to find out promising novel biomarkers for effective treatment. The goal of this study was to evaluate the biomarkers that can be potential therapeutic target and predict effective inhibitors to treat the metastatic stage of RCC. METHODS: We conducted transcriptomic profiling to identify differentially expressed genes associated with RCC...
September 30, 2016: BMC Cancer
Yan Wang, Jian-Shu Hu, Huang-Quan Lin, Tsz-Ming Ip, David Chi-Cheong Wan
BACKGROUND: Traditionally, molecular docking is primarily employed to screen pure compounds; the top-ranking chemicals are subsequently selected for experimental validation. Unlike synthetic chemicals, most natural products are commercially unavailable. The isolation and purification of each natural product is extremely time-consuming, which has restricted the screening of lead compounds from natural products. PURPOSE: We developed a protocol, Herbalog, to facilitate the identification of bioactive phytochemicals through molecular docking...
November 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Pakchisa Khonsuphap, Prasit Pavasant, Rizky Aditya Irwandi, Chidchanok Leethanakul, Anjalee Vacharaksa
BACKGROUND: Prostaglandin E2 (PGE2) accumulates in inflamed periodontal tissue and induces the receptor activator of nuclear factor kappa-B ligand (RANKL)-RANK-osteoprotegerin (OPG) signaling associated with bone resorption. Although oral epithelial cells maintain tissue homeostasis, the role of these cells in RANKL regulation remains unknown. METHODS: To mimic inflamed condition, RANKL upregulation in human mandibular osteoblast-like cells (HMOBs) were stimulated with PGE2...
October 20, 2016: Journal of Periodontology
Obdulia Rabal, Fernando Pastor, Helena Villanueva, Mario M Soldevilla, Sandra Hervas-Stubbs, Julen Oyarzabal
Complementing Systematic Evolution of Ligands by EXponential Enrichment (SELEX) technologies with in silico prediction of aptamer binders has attracted a lot of interest in the recent years. We propose a workflow involving 2D structure prediction, 3D RNA modeling using Rosetta and docking to the target protein with 3dRPC for: (i) prediction of the binding mode of our two previously reported potent (Kd < 50 nmol/l) murine TIM3 aptamers, and (ii) the prioritization of TIM3 aptamers that were enriched in the SELEX workflow...
October 18, 2016: Molecular Therapy. Nucleic Acids
Yves Claude Guillaume, Lydie Lethier, Claire André
TRAIL is a member of the TNF family of cytokines which induces apoptosis of cancer cells via its binding to its cognate receptors, DR5 a high affinity site and DR4 a site of low affinity. Our working group has recently demonstrated that nanovectorization of TRAIL with single wall carbon nanotubes (abbreviated NPT) enhanced TRAIL affinity to the high affinity site DR5 and increased pro apoptotic potential in different human tumor cell lines. In this paper, the DR4 low affinity site was immobilized on a chromatographic support and the effect of temperature on a wide temperature range 1°C-50°C was studied to calculate the thermodynamic parameters of the binding of TRAIL and NPT to DR4 and DR5 receptors...
October 12, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Hai Li, Dahang Zhao, Shengjing Wang, Jing Ding, Li Zhao
It has been confirmed that bone morphogenetic protein-9 (BMP-9) promotes the differentiation of osteoblasts. However, the ways in which BMP‑9 exerts its effects on the differentiation of osteoclasts and bone resorption remain to be elucidated. The present study was designed to investigate the roles and the molecular mechanism of BMP‑9 on the proliferation and differentiation of osteoclast precursors in vitro. Mouse spleen macrophages (RAW 264.7 cells) were cultured in the presence of receptor activator for nuclear factor‑κb ligand (RANKL) in vitro...
October 5, 2016: Molecular Medicine Reports
Linda J Fothergill, Brid Callaghan, Leni R Rivera, TinaMarie Lieu, Daniel P Poole, Hyun-Jung Cho, David M Bravo, John B Furness
TRPA1 is a ligand-activated cation channel found in the intestine and other tissues. Components of food that stimulate TRPA1 receptors (phytonutrients) include allyl isothiocyanate, cinnamaldehyde and linalool, but these may also act at other receptors. Cells lining the intestinal mucosa are immunoreactive for TRPA1 and Trpa1 mRNA occurs in mucosal extracts, suggesting that the TRPA1 receptor is the target for these agonists. However, in situ hybridisation reveals Trpa1 expression in 5-HT containing enteroendocrine cells, not enterocytes...
October 10, 2016: Nutrients
Pallab Kumar Borah, Sourav Chakraborty, Anupam N Jha, Sanchaita Rajkhowa, Raj Kumar Duary
ADAM metallopeptidase domain 17 (ADAM17) is an attractive target for the development of new anti-inflammatory drugs. We aimed to identify selective inhibitors of ADAM17 against matrix metalloproteinase enzymes (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13, and MMP-16) which have substantial structural similarity. Target proteins were docked with 29 anti-inflammatory natural molecule ligands and a known selective inhibitor IK682. The ligands were screened based on Lipinski rules, interaction with the ADAM17 active site cavity, and then ranked using the proportional odds model multinomial logistic regression...
October 5, 2016: Journal of Molecular Graphics & Modelling
Sergei Grudinin, Maria Kadukova, Andreas Eisenbarth, Simon Marillet, Frédéric Cazals
The 2015 D3R Grand Challenge provided an opportunity to test our new model for the binding free energy of small molecules, as well as to assess our protocol to predict binding poses for protein-ligand complexes. Our pose predictions were ranked 3-9 for the HSP90 dataset, depending on the assessment metric. For the MAP4K dataset the ranks are very dispersed and equal to 2-35, depending on the assessment metric, which does not provide any insight into the accuracy of the method. The main success of our pose prediction protocol was the re-scoring stage using the recently developed Convex-PL potential...
October 7, 2016: Journal of Computer-aided Molecular Design
Philip Prathipati, Chioko Nagao, Shandar Ahmad, Kenji Mizuguchi
The D3R 2015 grand drug design challenge provided a set of blinded challenges for evaluating the applicability of our protocols for pose and affinity prediction. In the present study, we report the application of two different strategies for the two D3R protein targets HSP90 and MAP4K4. HSP90 is a well-studied target system with numerous co-crystal structures and SAR data. Furthermore the D3R HSP90 test compounds showed high structural similarity to existing HSP90 inhibitors in BindingDB. Thus, we adopted an integrated docking and scoring approach involving a combination of both pharmacophoric and heavy atom similarity alignments, local minimization and quantitative structure activity relationships modeling, resulting in the reasonable prediction of pose [with the root mean square deviation (RMSD) values of 1...
October 6, 2016: Journal of Computer-aided Molecular Design
Son Tung Ngo, Huynh Minh Hung, Minh Tho Nguyen
The fast pulling ligand (FPL) out of binding cavity using non-equilibrium molecular dynamics (MD) simulations was demonstrated to be a rapid, accurate and low CPU demand method for the determination of the relative binding affinities of a large number of HIV-1 protease (PR) inhibitors. In this approach, the ligand is pulled out of the binding cavity of the protein using external harmonic forces, and the work of pulling force corresponds to the relative binding affinity of HIV-1 PR inhibitor. The correlation coefficient between the pulling work and the experimental binding free energy of R=-0...
December 5, 2016: Journal of Computational Chemistry
Sergio Ruiz-Carmona, Xavier Barril
Novel methods for drug discovery are constantly under development and independent exercises to test and validate them for different goals are extremely useful. The drug discovery data resource (D3R) Grand Challenge 2015 offers an excellent opportunity as an external assessment and validation experiment for Computer-Aided Drug Discovery methods. The challenge comprises two protein targets and prediction tests: binding mode and ligand ranking. We have faced both of them with the same strategy: pharmacophore-guided docking followed by dynamic undocking (a new method tested experimentally here) and, where possible, critical assessment of the results based on pre-existing information...
October 5, 2016: Journal of Computer-aided Molecular Design
J H Sun, N Fan, Y Zhang
In this study, we investigated the correlation between serum chemokine (C-C motif) ligand 18 (CCL-18) and the prognosis as well as clinical characteristics of breast cancer. Blood samples from 207 breast cancer patients, 126 individuals with benign breast tumors, and 93 healthy women were collected. Serum CCL-18 expression was detected by enzyme-linked immunosorbent assay. Mann-Whitney's U tests were carried out to analyze the relationship between serum CCL-18 and clinicopathological variables. The Kaplan-Meier method was used to evaluate the overall survival (OS), whereas differences between groups were analyzed by log-rank tests...
September 9, 2016: Genetics and Molecular Research: GMR
Toni Ibrahim, Marianna Ricci, Emanuela Scarpi, Alberto Bongiovanni, Rossana Ricci, Nada Riva, Chiara Liverani, Alessandro De Vita, Federico La Manna, Devil Oboldi, Patrizia Serra, Flavia Foca, Lorenzo Cecconetto, Dino Amadori, Laura Mercatali
Bone metastases are a frequent event in patients with solid tumors. Although great advances have been made in the treatment of these patients, the identification of novel, accurate indicators of bone response would greatly facilitate the clinical management of the disease. The receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) signaling pathway is significantly involved in bone metastasis formation. The main aim of the present study was to evaluate the role of circulating RANK, RANKL and OPG levels in predicting bone response...
October 2016: Oncology Letters
Symon Gathiaka, Shuai Liu, Michael Chiu, Huanwang Yang, Jeanne A Stuckey, You Na Kang, Jim Delproposto, Ginger Kubish, James B Dunbar, Heather A Carlson, Stephen K Burley, W Patrick Walters, Rommie E Amaro, Victoria A Feher, Michael K Gilson
The Drug Design Data Resource (D3R) ran Grand Challenge 2015 between September 2015 and February 2016. Two targets served as the framework to test community docking and scoring methods: (1) HSP90, donated by AbbVie and the Community Structure Activity Resource (CSAR), and (2) MAP4K4, donated by Genentech. The challenges for both target datasets were conducted in two stages, with the first stage testing pose predictions and the capacity to rank compounds by affinity with minimal structural data; and the second stage testing methods for ranking compounds with knowledge of at least a subset of the ligand-protein poses...
September 30, 2016: Journal of Computer-aided Molecular Design
Jessica Chen, Peter Smerdely
: Hypocalcaemia following denosumab therapy can be observed in older adults. This is more common if their pre-treatment corrected serum calcium concentrations are less than 2.28 mmol/L. Denosumab remains a safe treatment in older people but we recommend a cautious approach in people at risk. INTRODUCTION: Previous studies have indicated that denosumab, an anti-RANK ligand (RANKL) monoclonal antibody, for treatment of osteoporosis is well-tolerated. There is little data specifically regarding its adverse effect profile in a hospitalised older person...
September 28, 2016: Osteoporosis International
Hassan Y Ebrahim, Mohamed M Mohyeldin, Mohammad M Hailat, Khalid A El Sayed
(1S,2E,4S,6R,7E,11E)-2,7,11-Cembratriene-4,6-diol (1) and its 4-epi-analog (2) are the cembranoid precursors to several key flavor ingredients in most Nicotiana (tobacco) species. Nearly 40-60% of 1 and 2 are purposely degraded during the commercial tobacco fermentation. However, 1 and 2 display promising bioactivities, including anticancer. Breast cancer is the most diagnosed cancer in women and ranked second female disease killer. The receptor tyrosine kinase c-Met correlates with aggressiveness of certain breast cancer phenotypes and thus considered a valid therapeutic target...
September 13, 2016: Bioorganic & Medicinal Chemistry
Shanshan Liu, Timothy O Street
The molecular chaperone Hsp90 facilitates the folding and modulates activation of diverse substrate proteins. Unlike other heat shock proteins such as Hsp60 and Hsp70, Hsp90 plays critical regulatory roles by maintaining active states of kinases, many of which are overactive in cancer cells. Four Hsp90 paralogs are expressed in eukaryotic cells: Hsp90α/β (in the cytosol), Grp94 (in the endoplasmic reticulum), Trap1 (in mitochondria). Although numerous Hsp90 inhibitors are being tested in cancer clinical trials, little is known about why different Hsp90 inhibitors show specificity among Hsp90 paralogs...
September 26, 2016: Protein Science: a Publication of the Protein Society
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