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Blind Docking

Giuseppe Sciortino, José-Emilio Sánchez-Aparicio, Jaime Rodríguez-Guerra Pedregal, Eugenio Garribba, Jean-Didier Maréchal
In an organism, cisplatin and its derivatives are known to interact with proteins besides their principal DNA target. These off-target interactions have major therapeutic consequences including undesired side effects, loss of bioavailability and emergence of resistance. Insulin is one of the prototypical protein targets of platinum drugs as it has been seen to be involved in bioavailability reduction and might also determine resistance in certain cancer lines. However, despite the interest in understanding the nature of the oxaliplatin-insulin adducts, no 3D models have been achieved so far...
February 6, 2019: Metallomics: Integrated Biometal Science
Piyush Agrawal, Harinder Singh, Hemant Kumar Srivastava, Sandeep Singh, Gaurav Kishore, Gajendra P S Raghava
BACKGROUND: Molecular docking studies on protein-peptide interactions are a challenging and time-consuming task because peptides are generally more flexible than proteins and tend to adopt numerous conformations. There are several benchmarking studies on protein-protein, protein-ligand and nucleic acid-ligand docking interactions. However, a series of docking methods is not rigorously validated for protein-peptide complexes in the literature. Considering the importance and wide application of peptide docking, we describe benchmarking of 6 docking methods on 133 protein-peptide complexes having peptide length between 9 to 15 residues...
February 4, 2019: BMC Bioinformatics
Mónika Bálint, István Horváth, Nikolett Mészáros, Csaba Hetényi
Histones serve as protein spools for winding the DNA in the nucleosome. High variability of their post-translational modifications result in a unique code system often responsible for the pathomechanisms of epigenetics-based diseases. Decoding is performed by reader proteins via complex formation with the N-terminal peptide tails of histones. Determination of structures of histone-reader complexes would be a key to unravel the histone code and the design of new drugs. However, the large number of possible histone complex variations imposes a true challenge for experimental structure determination techniques...
January 19, 2019: International Journal of Molecular Sciences
Mariano Andrea Scorciapino, Giuliano Malloci, Ilaria Serra, Stefan Milenkovic, Lucile Moynié, James H Naismith, Eric Desarbre, Malcolm G P Page, Matteo Ceccarelli
Nuclear magnetic resonance and infrared spectroscopy have been used to investigate the formation of complexes of BAL30072 with Fe3+ and Ga3+ in solution and to collect geometrical parameters supporting reliable 3D structure models. Structural models for the ligand-metal complexes with different stoichiometries have been characterized using density functional theory calculations. Blind ensemble docking to the PiuA receptor from P. aeruginosa was performed for the different complexes to compare binding affinities and statistics of the residues most frequently contacted...
January 11, 2019: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
Zied Gaieb, Conor D Parks, Michael Chiu, Huanwang Yang, Chenghua Shao, W Patrick Walters, Millard H Lambert, Neysa Nevins, Scott D Bembenek, Michael K Ameriks, Tara Mirzadegan, Stephen K Burley, Rommie E Amaro, Michael K Gilson
The Drug Design Data Resource aims to test and advance the state of the art in protein-ligand modeling by holding community-wide blinded, prediction challenges. Here, we report on our third major round, Grand Challenge 3 (GC3). Held 2017-2018, GC3 centered on the protein Cathepsin S and the kinases VEGFR2, JAK2, p38-α, TIE2, and ABL1, and included both pose-prediction and affinity-ranking components. GC3 was structured much like the prior challenges GC2015 and GC2. First, Stage 1 tested pose prediction and affinity ranking methods; then all available crystal structures were released, and Stage 2 tested only affinity rankings, now in the context of the available structures...
January 2019: Journal of Computer-aided Molecular Design
Maria A Brehm, Ulrike Klemm, Christoph Rehbach, Nina Erdmann, Katra Kolšek, Hongying Lin, Camilo Aponte-Santamaría, Frauke Gräter, Bernhard H Rauch, Andrew M Riley, Georg W Mayr, Barry V L Potter, Sabine Windhorst
The inositol phosphates, InsP5 and InsP6 , have recently been identified as binding partners of fibrinogen, which is critically involved in hemostasis by crosslinking activated platelets at sites of vascular injury. Here, we investigated the putative physiological role of this interaction and found that platelets increase their InsP6 concentration upon stimulation with the PLC-activating agonists thrombin, collagen I and ADP and present a fraction of it at the outer plasma membrane. Cone and plate analysis in whole blood revealed that InsP6 specifically increases platelet aggregate size...
December 14, 2018: Biochemical Pharmacology
Li-Qiong Zhang, Hao Cui, Yong-Bin Yu, Huan-Qi Shi, Yuan Zhou, Mei-Jiao Liu
Retinal neovascularization occurs in various ocular disorders including proliferative diabetic retinopathy and secondary neovascular glaucoma, resulting in blindness. This paper aims to investigate the effect of microRNA-141-3p (miR-141-3p) on retinal neovascularization and retinal ganglion cells (RGCs) in glaucoma mice through the Docking protein 5 (DOK5)-mediated mitogen-activated protein kinase (MAPK) signaling pathway. Chip retrieval and difference analysis were used for the potential mechanism of miR-141-3p on glaucoma...
December 4, 2018: Journal of Cellular Physiology
Ruben Cloete, Erika Kapp, Jacques Joubert, Alan Christoffels, Sarel F Malan
Mycobacterial efflux pumps play a major role in the emergence of antimycobacterial drug resistance. Of particular interest is the proteinaceous multi-drug efflux pump protein Rv1258c that encodes a tetracycline/aminoglycoside resistance (TAP-2)-like efflux pump which is active in susceptible and drug resistant Mycobacterium tuberculosis. Rv1258c is implicated in drug resistance to numerous antimycobacterials including first line drugs rifampicin and isoniazid as well as fluoroquinolone and aminoglycoside antibiotic classes...
2018: PloS One
Kalli Kappel, Rhiju Das
RNA-protein complexes underlie numerous cellular processes including translation, splicing, and posttranscriptional regulation of gene expression. The structures of these complexes are crucial to their functions but often elude high-resolution structure determination. Computational methods are needed that can integrate low-resolution data for RNA-protein complexes while modeling de novo the large conformational changes of RNA components upon complex formation. To address this challenge, we describe RNP-denovo, a Rosetta method to simultaneously fold-and-dock RNA to a protein surface...
October 25, 2018: Structure
Naohiro Nishikawa, Kyungreem Han, Xiongwu Wu, Florentina Tofoleanu, Bernard R Brooks
We calculate the absolute binding free energies of tetra-methylated octa-acids host-guest systems as a part of the SAMPL6 blind challenge (receipt ID vq30p). We employed two different free energy simulation methods, i.e., the umbrella sampling (US) and double decoupling method (DDM). The US method was used with the weighted histogram analysis method (WHAM) (US-WHAM scheme). In the DDM scheme, Hamiltonian replica-exchange method (HREM) was combined with the Bennett acceptance ratio (BAR) (HREM-BAR scheme). We obtained initial binding poses via molecular docking using GalaxyDock-HG program, which is developed for the SAMPL challenge...
October 2018: Journal of Computer-aided Molecular Design
Nikhil Agrawal, Md Summon Hossain, Adam A Skelton, Kambadur Muralidhar, Sandeep Kaushik
l-Gulonate dehydrogenase (GuDH) is a crucial enzyme in the non-phosphorylated sugar metabolism or glucuronate-xylulose (GX) pathway. Some naturally occurring compounds inhibit GuDH. Ascorbic acid is one of such inhibitors for GuDH. However, the exact mechanism by which ascorbic acid inhibits GuDH is still unknown. In this study, we try to investigate GuDH inhibition using computational approaches by generating a model for buffalo GuDH. We used this model to perform blind dockings of ascorbic acid to GuDH. Some docked conformations of ascorbic acid bind near Asp39 and have steric clashes with crystal structure conformation of NADH...
September 27, 2018: Computational Biology and Chemistry
Anupriya Sadhasivam, Umashankar Vetrivel
Chlamydia trachomatis (C.t) is a gram-negative obligate intracellular bacteria, which is a major causative of infectious blindness and sexually transmitted diseases. A surge in multidrug resistance among chlamydial species has posed a challenge to adopt alternative drug targeting strategies. Recently, in C.t, L,L-diaminopimelate aminotransferase (CtDAP-AT) is proven to be a potential drug target due its essential role in cell survival and host nonspecificity. Hence, in this study, a multilevel precision-based virtual screening of CtDAP-AT was performed to identify potential inhibitors, wherein, an integrative stringent scoring and filtration were performed by coupling, glide docking score, binding free energy, ADMET (absorption, distribution, metabolism, and excretion, toxicity) prediction, density functional theory (quantum mechanics), and molecular dynamics simulation (molecular mechanics)...
October 10, 2018: Journal of Cellular Biochemistry
Kinga Kasperkiewicz, Michal B Ponczek, Elzbieta Budzisz
BACKGROUND: Scientists still look for new drugs, which have anticoagulant properties. This is so important because existing anticoagulant drugs give many side effects, for example major bleeding. In this study we examined nine coumarin derivatives - candidates to be future antithrombotic drugs, which were synthetized and crystallized in our previous paper. METHODS: Here we show the fluorescence and fluorescence quenching of coumarin derivatives with di- or trimethoxybenzylamine moieties in C-3 position...
June 15, 2018: Pharmacological Reports: PR
Martino Bertoni, Patrick Aloy
Multi-protein machines are responsible for most cellular tasks, and many efforts have been invested in the systematic identification and characterization of thousands of these macromolecular assemblies. However, unfortunately, the (quasi) atomic details necessary to understand their function are available only for a tiny fraction of the known complexes. The computational biology community is developing strategies to integrate structural data of different nature, from electron microscopy to X-ray crystallography, to model large molecular machines, as it has been done for individual proteins and interactions with remarkable success...
October 19, 2018: Journal of Molecular Biology
Xibing He, Viet H Man, Beihong Ji, Xiang-Qun Xie, Junmei Wang
We participated in the Cathepsin S (CatS) sub-challenge of the Drug Design Data Resource (D3R) Grand Challenge 3 (GC3) in 2017 to blindly predict the binding poses of 24 CatS-bound ligands, the binding affinity ranking of 136 ligands, and the binding free energies of a subset of 33 ligands in Stage 1A and Stage 2. Our submitted predictions ranked relatively well compared to the submissions from other participants. Here we present our methodologies used in the challenge. For the binding pose prediction, we employed the Glide module in the Schrodinger Suite 2017 and AutoDock Vina...
September 14, 2018: Journal of Computer-aided Molecular Design
T Tibaut, T Tomašič, V Hodnik, M Anderluh, S Pintar, M Novič, D Turk
A structure-based approach is applied for the development of inhibitors of bacterial N-acetyglucosaminidase (autolysin). Autolysins are enzymes involved in the degradation of peptidoglycan and therefore participate in bacterial cell growth and different lysis phenomena. Several studies indicate that by the inhibition of autolysins, and consequently of bacterial cell division, antibacterial activity can be obtained, thus paving the road to a novel group of therapeutics against human pathogens. As crystal structures of the autolysin E (AtlE)-ligand complexes were obtained in our laboratories, fragment-based virtual screening was the method of choice for the initial studies...
September 2018: SAR and QSAR in Environmental Research
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)...
December 5, 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...
September 2018: Journal of Pediatric Orthopedics
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