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Blind Docking

Polo C-H Lam, Ruben Abagyan, Maxim Totrov
In context of D3R Grand Challenge 3 we have investigated several ligand activity prediction protocols that combined elements of a physics-based energy function (ICM VLS score) and the knowledge-based Atomic Property Field 3D QSAR approach. Activity prediction models utilized poses produced by ICM-Dock with ligand bias and 4D receptor conformational ensembles (LigBEnD). Hybrid APF/P (APF/Physics) models were superior to pure physics- or knowledge-based models in our preliminary tests using rigorous three-fold clustered cross-validation and later proved successful in the blind prediction for D3R GC3 sets, consistently performing well across four different targets...
August 9, 2018: Journal of Computer-aided Molecular Design
Seyed Mohammad Bagher Hosseini Ghazvini, Parvin Safari, Akbar Mobinikhaledi, Hassan Moghanian, Hassan Rasouli
A new compound named 7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde oxime (7-Oxime) was synthesized and characterized by FT-IR, FT-Raman, 1 H NMR and 13 C NMR techniques. The conformer possibilities were studied to find the most stable conformer and its molecular geometry. Then, the dimer form of the most stable monomer was built and optimized. Density functional theory (DFT) B3LYP method with 6-311++G(d,p) basis set was applied to analyze the molecular electrostatic potential (MEP), HOMO and LUMO orbitals, the vibrational wavenumbers, the infrared intensities, the Raman scattering activities and several thermodynamic properties (at different temperatures)...
July 6, 2018: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
María Francisca Matus, Martín Ludueña, Cristian Vilos, Iván Palomo, Marcelo M Mariscal
Nanotherapeutics is a promising field for numerous diseases and represents the forefront of modern medicine. In the present work, full atomistic computer simulations were applied to study poly(lactic acid) (PLA) nanoparticles conjugated with polyethylene glycol (PEG). The formation of this complex system was simulated using the reactive polarizable force field (ReaxFF). A full picture of the morphology, charge and functional group distribution is given. We found that all terminal groups (carboxylic acid, methoxy and amino) are randomly distributed at the surface of the nanoparticles...
2018: Beilstein Journal of Nanotechnology
Nakul S Talathi, Nancy A Chauvin, Wudbhav N Sankar
BACKGROUND: It has been suggested that the femoral head can "dock" deeper into the acetabulum after initial closed reduction (CR) for developmental dysplasia of the hip (DDH). The purpose of this study was to quantify the interval change in femoral head position between immediate postoperative magnetic resonance imaging (MRI) and follow-up imaging at ~3 weeks. METHODS: A retrospective review of 29 patients (30 hips) who underwent CR and spica casting for DDH was conducted...
June 18, 2018: Journal of Pediatric Orthopedics
Qi Wu, Zhenling Peng, Yang Zhang, Jianyi Yang
The identification of protein-ligand binding sites is critical to protein function annotation and drug discovery. The consensus algorithm COACH developed by us represents one of the most efficient approaches to protein-ligand binding sites prediction. One of the most commonly seen issues with the COACH prediction are the low quality of the predicted ligand-binding poses, which usually have severe steric clashes to the protein structure. Here, we present COACH-D, an enhanced version of COACH by utilizing molecular docking to refine the ligand-binding poses...
July 2, 2018: Nucleic Acids Research
Pei Zhou, Bowen Jin, Hao Li, Sheng-You Huang
Protein-peptide interactions are crucial in many cellular functions. Therefore, determining the structure of protein-peptide complexes is important for understanding the molecular mechanism of related biological processes and developing peptide drugs. HPEPDOCK is a novel web server for blind protein-peptide docking through a hierarchical algorithm. Instead of running lengthy simulations to refine peptide conformations, HPEPDOCK considers the peptide flexibility through an ensemble of peptide conformations generated by our MODPEP program...
July 2, 2018: Nucleic Acids Research
Nicholas A Marze, Shourya S Roy Burman, William Sheffler, Jeffrey J Gray
Motivation: Binding-induced conformational changes challenge current computational docking algorithms by exponentially increasing the conformational space to be explored. To restrict this search to relevant space, some computational docking algorithms exploit the inherent flexibility of the protein monomers to simulate conformational selection from pre-generated ensembles. As the ensemble size expands with increased flexibility, these methods struggle with efficiency and high false positive rates...
April 30, 2018: Bioinformatics
Tomohiro Ban, Masahito Ohue, Yutaka Akiyama
The identification of comprehensive drug-target interactions is important in drug discovery. Although numerous computational methods have been developed over the years, a gold standard technique has not been established. Computational ligand docking and structure-based drug design allow researchers to predict the binding affinity between a compound and a target protein, and thus, they are often used to virtually screen compound libraries. In addition, docking techniques have also been applied to the virtual screening of target proteins (inverse docking) to predict target proteins of a drug candidate...
April 2018: Computational Biology and Chemistry
Sandra Álvarez-Carretero, Niki Pavlopoulou, James Adams, Jane Gilsenan, Lydia Tabernero
The use of computational tools for virtual screening provides a cost-efficient approach to select starting points for drug development. We have developed VSpipe, a user-friendly semi-automated pipeline for structure-based virtual screening. VSpipe uses the existing tools AutoDock and OpenBabel together with software developed in-house, to create an end-to-end virtual screening workflow ranging from the preparation of receptor and ligands to the visualisation of results. VSpipe is efficient and flexible, allowing the users to make choices at different steps, and it is amenable to use in both local and cluster mode...
February 7, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Di Wu, Dayu Liu, Yin Zhang, Zhen Zhang, Hui Li
The interaction between benproperine (BEN) and human serum albumin (HSA) has been simulatively and experimentally investigated based on docking, fluorometric, thermodynamic, and spectroscopic approach. The blind Autodock docking study first recognized the hydrophobic cavity of HSA at Domain IB as the probable binding site for BEN. BEN bound to HSA via a static quenching mechanism, resulting in the formation of BEN-HSA complex confirmed by fluorescence quenching and time-resolved fluorescence. Fluorescence titration and isothermal titration calorimetry (ITC) revealed that the binding mode between BEN and HSA owning moderate affinity (binding constant at 104 magnitude) was mainly driven by electrostatic attraction and hydrophobic interaction...
February 25, 2018: European Journal of Medicinal Chemistry
Dustin J E Huard, Vincent M Crowley, Yuhong Du, Ricardo A Cordova, Zheying Sun, Moya O Tomlin, Chad A Dickey, John Koren, Laura Blair, Haian Fu, Brian S J Blagg, Raquel L Lieberman
Gain-of-function mutations within the olfactomedin (OLF) domain of myocilin result in its toxic intracellular accumulation and hasten the onset of open-angle glaucoma. The absence of myocilin does not cause disease; therefore, strategies aimed at eliminating myocilin could lead to a successful glaucoma treatment. The endoplasmic reticulum Hsp90 paralog Grp94 accelerates OLF aggregation. Knockdown or pharmacological inhibition of Grp94 in cells facilitates clearance of mutant myocilin via a non-proteasomal pathway...
April 20, 2018: ACS Chemical Biology
José Pedro Cerón-Carrasco, Horacio Pérez-Sánchez, José Zúñiga, Alberto Requena
The human epidermal growth factor receptor 2 (HER2) is overexpressed in about a third of breast cancer patients, with a strong involvement of the cyclooxygenase-2 (COX-2) enzyme in the tumor progress. HER2 and COX-2 are consequently potential targets for inhibiting carcionogenesis. Herceptin (trastuzumab) is an antibody that partially blocks HER2-positive cancers at their initial stage. Unfortunately, the overall response rate to the single treatment with this antibody is still modest, and therefore, it needs to be improved by combining several chemotherapeutic agents...
February 22, 2018: Journal of Physical Chemistry. B
Mónika Bálint, Norbert Jeszenői, István Horváth, David van der Spoel, Csaba Hetényi
BACKGROUND: Targets with multiple (prerequisite or allosteric) binding sites have an increasing importance in drug design. Experimental determination of atomic resolution structures of ligands weakly bound to multiple binding sites is often challenging. Blind docking has been widely used for fast mapping of the entire target surface for multiple binding sites. Reliability of blind docking is limited by approximations of hydration models, simplified handling of molecular flexibility, and imperfect search algorithms...
December 28, 2017: Journal of Cheminformatics
Rania S Sulaiman, Bomina Park, Sardar Pasha Sheik Pran Babu, Yubing Si, Rakshin Kharwadkar, Sayak K Mitter, Bit Lee, Wei Sun, Xiaoping Qi, Michael E Boulton, Samy O Meroueh, Xiang Fei, Seung-Yong Seo, Timothy W Corson
The standard-of-care therapeutics for the treatment of ocular neovascular diseases like wet age-related macular degeneration (AMD) are biologics targeting vascular endothelial growth factor signaling. There are currently no FDA approved small molecules for treating these blinding eye diseases. Therefore, therapeutic agents with novel mechanisms are critical to complement or combine with existing approaches. Here, we identified soluble epoxide hydrolase (sEH), a key enzyme for epoxy fatty acid metabolism, as a target of an antiangiogenic homoisoflavonoid, SH-11037...
January 19, 2018: ACS Chemical Biology
Ting Wang, Haiguang Liu, Yong Duan
The community-wide blind prediction of G-protein coupled receptor (GPCR) structures and ligand docking has been conducted three times and the quality of the models was primarily assessed by the accuracy of ligand binding modes. The seven transmembrane (TM) helices of the receptors were taken as a whole; thus the model quality within the 7TM domains has not been evaluated. Here we evaluate the 7TM domain structures in the models submitted for the last round of prediction - GPCR Dock 2013. Applying the 7 × 7 RMSD matrix analysis described in our prior work, we show that the models vary widely in prediction accuracy of the 7TM structures, exhibiting diverse structural differences from the targets...
March 2018: Journal of Structural Biology
Nafisa M Hassan, Amr A Alhossary, Yuguang Mu, Chee-Keong Kwoh
"Virtual Screening" is a common step of in silico drug design, where researchers screen a large library of small molecules (ligands) for interesting hits, in a process known as "Docking". However, docking is a computationally intensive and time-consuming process, usually restricted to small size binding sites (pockets) and small number of interacting residues. When the target site is not known (blind docking), researchers split the docking box into multiple boxes, or repeat the search several times using different seeds, and then merge the results manually...
November 13, 2017: Scientific Reports
Matthew P Baumgartner, David A Evans
Two of the major ongoing challenges in computational drug discovery are predicting the binding pose and affinity of a compound to a protein. The Drug Design Data Resource Grand Challenge 2 was developed to address these problems and to drive development of new methods. The challenge provided the 2D structures of compounds for which the organizers help blinded data in the form of 35 X-ray crystal structures and 102 binding affinity measurements and challenged participants to predict the binding pose and affinity of the compounds...
January 2018: Journal of Computer-aided Molecular Design
Christina Athanasiou, Sofia Vasilakaki, Dimitris Dellis, Zoe Cournia
Computer-aided drug design has become an integral part of drug discovery and development in the pharmaceutical and biotechnology industry, and is nowadays extensively used in the lead identification and lead optimization phases. The drug design data resource (D3R) organizes challenges against blinded experimental data to prospectively test computational methodologies as an opportunity for improved methods and algorithms to emerge. We participated in Grand Challenge 2 to predict the crystallographic poses of 36 Farnesoid X Receptor (FXR)-bound ligands and the relative binding affinities for two designated subsets of 18 and 15 FXR-bound ligands...
January 2018: Journal of Computer-aided Molecular Design
Carolina de la Guardia, Mario Quijada, Ricardo Lleonart
Dengue virus is a growing public health threat that affects hundreds of million peoples every year and leave huge economic and social damage. The virus is transmitted by mosquitoes and the incidence of the disease is increasing, among other causes, due to the geographical expansion of the vector's range and the lack of effectiveness in public health interventions in most prevalent countries. So far, no highly effective vaccine or antiviral has been developed for this virus. Here we employed phage display technology to identify peptides able to block the DENV2...
2017: Advances in Virology
Soumendranath Bhakat, Emil Åberg, Pär Söderhjelm
Advanced molecular docking methods often aim at capturing the flexibility of the protein upon binding to the ligand. In this study, we investigate whether instead a simple rigid docking method can be applied, if combined with multiple target structures to model the backbone flexibility and molecular dynamics simulations to model the sidechain and ligand flexibility. The methods are tested for the binding of 35 ligands to FXR as part of the first stage of the Drug Design Data Resource (D3R) Grand Challenge 2 blind challenge...
January 2018: Journal of Computer-aided Molecular Design
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