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Journal of Computer-aided Molecular Design

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https://www.readbyqxmd.com/read/29340866/-in-silico-study-of-the-binding-of-two-novel-antagonists-to-the-nociceptin-receptor
#1
Stefano Della Longa, Alessandro Arcovito
Antagonists of the nociceptin receptor (NOP) are raising interest for their possible clinical use as antidepressant drugs. Recently, the structure of NOP in complex with some piperidine-based antagonists has been revealed by X-ray crystallography. In this study, a multi-flexible docking (MF-docking) procedure, i.e. docking to multiple receptor conformations extracted by preliminary molecular dynamics trajectories, together with hybrid quantum mechanics/molecular mechanics (QM/MM) simulations have been carried out to provide the binding mode of two novel NOP antagonists, one of them selective (BTRX-246040, formerly named LY-2940094) and one non selective (AT-076), i...
January 16, 2018: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29340865/design-of-a-tripartite-network-for-the-prediction-of-drug-targets
#2
Ryo Kunimoto, Jürgen Bajorath
Drug-target networks have aided in many target prediction studies aiming at drug repurposing or the analysis of side effects. Conventional drug-target networks are bipartite. They contain two different types of nodes representing drugs and targets, respectively, and edges indicating pairwise drug-target interactions. In this work, we introduce a tripartite network consisting of drugs, other bioactive compounds, and targets from different sources. On the basis of analog relationships captured in the network and so-called neighbor targets of drugs, new drug targets can be inferred...
January 16, 2018: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29335872/disruptor-of-telomeric-silencing-1-like-dot1l-disclosing-a-new-class-of-non-nucleoside-inhibitors-by-means-of-ligand-based-and-structure-based-approaches
#3
Manuela Sabatino, Dante Rotili, Alexandros Patsilinakos, Mariantonietta Forgione, Daniela Tomaselli, Fréderic Alby, Paola B Arimondo, Antonello Mai, Rino Ragno
Chemical inhibition of chromatin-mediated signaling involved proteins is an established strategy to drive expression networks and alter disease progression. Protein methyltransferases are among the most studied proteins in epigenetics and, in particular, disruptor of telomeric silencing 1-like (DOT1L) lysine methyltransferase plays a key role in MLL-rearranged acute leukemia Selective inhibition of DOT1L is an established attractive strategy to breakdown aberrant H3K79 methylation and thus overexpression of leukemia genes, and leukemogenesis...
January 15, 2018: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29335871/validation-of-tautomeric-and-protomeric-binding-modes-by-free-energy-calculations-a-case-study-for-the-structure-based-optimization-of-d-amino-acid-oxidase-inhibitors
#4
Zoltán Orgován, György G Ferenczy, Thomas Steinbrecher, Bence Szilágyi, Dávid Bajusz, György M Keserű
Optimization of fragment size D-amino acid oxidase (DAAO) inhibitors was investigated using a combination of computational and experimental methods. Retrospective free energy perturbation (FEP) calculations were performed for benzo[d]isoxazole derivatives, a series of known inhibitors with two potential binding modes derived from X-ray structures of other DAAO inhibitors. The good agreement between experimental and computed binding free energies in only one of the hypothesized binding modes strongly support this bioactive conformation...
January 15, 2018: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29306979/discovering-new-pi3k%C3%AE-inhibitors-with-a-strategy-of-combining-ligand-based-and-structure-based-virtual-screening
#5
Miao Yu, Qiong Gu, Jun Xu
PI3Kα is a promising drug target for cancer chemotherapy. In this paper, we report a strategy of combing ligand-based and structure-based virtual screening to identify new PI3Kα inhibitors. First, naïve Bayesian (NB) learning models and a 3D-QSAR pharmacophore model were built based upon known PI3Kα inhibitors. Then, the SPECS library was screened by the best NB model. This resulted in virtual hits, which were validated by matching the structures against the pharmacophore models. The pharmacophore matched hits were then docked into PI3Kα crystal structures to form ligand-receptor complexes, which are further validated by the Glide-XP program to result in structural validated hits...
January 6, 2018: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29280033/a-combined-fisher-and-laplacian-score-for-feature-selection-in-qsar-based-drug-design-using-compounds-with-known-and-unknown-activities
#6
Mohammad Amin Valizade Hasanloei, Razieh Sheikhpour, Mehdi Agha Sarram, Elnaz Sheikhpour, Hamdollah Sharifi
Quantitative structure-activity relationship (QSAR) is an effective computational technique for drug design that relates the chemical structures of compounds to their biological activities. Feature selection is an important step in QSAR based drug design to select the most relevant descriptors. One of the most popular feature selection methods for classification problems is Fisher score which aim is to minimize the within-class distance and maximize the between-class distance. In this study, the properties of Fisher criterion were extended for QSAR models to define the new distance metrics based on the continuous activity values of compounds with known activities...
December 26, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29264790/congestion-game-scheduling-for-virtual-drug-screening-optimization
#7
Natalia Nikitina, Evgeny Ivashko, Andrei Tchernykh
In virtual drug screening, the chemical diversity of hits is an important factor, along with their predicted activity. Moreover, interim results are of interest for directing the further research, and their diversity is also desirable. In this paper, we consider a problem of obtaining a diverse set of virtual screening hits in a short time. To this end, we propose a mathematical model of task scheduling for virtual drug screening in high-performance computational systems as a congestion game between computational nodes to find the equilibrium solutions for best balancing the number of interim hits with their chemical diversity...
December 20, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29260350/atomistic-computer-simulations-on-multi-loaded-pamam-dendrimers-a-comparison-of-amine-and-hydroxyl-terminated-dendrimers
#8
Farideh Badalkhani-Khamseh, Azadeh Ebrahim-Habibi, Nasser L Hadipour
Poly(amidoamine) (PAMAM) dendrimers have been extensively studied as delivery vectors in biomedical applications. A limited number of molecular dynamics (MD) simulation studies have investigated the effect of surface chemistry on therapeutic molecules loading, with the aim of providing insights for biocompatibility improvement and increase in drug loading capacity of PAMAM dendrimers. In this work, fully atomistic MD simulations were employed to study the association of 5-Fluorouracil (5-FU) with amine (NH2)- and hydroxyl (OH)-terminated PAMAM dendrimers of generations 3 and 4 (G3 and G4)...
December 19, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29234997/learning-epistatic-interactions-from-sequence-activity-data-to-predict-enantioselectivity
#9
Julian Zaugg, Yosephine Gumulya, Alpeshkumar K Malde, Mikael Bodén
Enzymes with a high selectivity are desirable for improving economics of chemical synthesis of enantiopure compounds. To improve enzyme selectivity mutations are often introduced near the catalytic active site. In this compact environment epistatic interactions between residues, where contributions to selectivity are non-additive, play a significant role in determining the degree of selectivity. Using support vector machine regression models we map mutations to the experimentally characterised enantioselectivities for a set of 136 variants of the epoxide hydrolase from the fungus Aspergillus niger (AnEH)...
December 12, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29204945/d3r-grand-challenge-2-blind-prediction-of-protein-ligand-poses-affinity-rankings-and-relative-binding-free-energies
#10
Zied Gaieb, Shuai Liu, Symon Gathiaka, Michael Chiu, Huanwang Yang, Chenghua Shao, Victoria A Feher, W Patrick Walters, Bernd Kuhn, Markus G Rudolph, Stephen K Burley, Michael K Gilson, Rommie E Amaro
The Drug Design Data Resource (D3R) ran Grand Challenge 2 (GC2) from September 2016 through February 2017. This challenge was based on a dataset of structures and affinities for the nuclear receptor farnesoid X receptor (FXR), contributed by F. Hoffmann-La Roche. The dataset contained 102 IC50 values, spanning six orders of magnitude, and 36 high-resolution co-crystal structures with representatives of four major ligand classes. Strong global participation was evident, with 49 participants submitting 262 prediction submission packages in total...
December 4, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29189937/bioactive-focus-in-conformational-ensembles-a-pluralistic-approach
#11
Matthew Habgood
Computational generation of conformational ensembles is key to contemporary drug design. Selecting the members of the ensemble that will approximate the conformation most likely to bind to a desired target (the bioactive conformation) is difficult, given that the potential energy usually used to generate and rank the ensemble is a notoriously poor discriminator between bioactive and non-bioactive conformations. In this study an approach to generating a focused ensemble is proposed in which each conformation is assigned multiple rankings based not just on potential energy but also on solvation energy, hydrophobic or hydrophilic interaction energy, radius of gyration, and on a statistical potential derived from Cambridge Structural Database data...
November 30, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29177929/structure-and-dynamics-of-mesophilic-variants-from-the-homing-endonuclease-i-dmoi
#12
Josephine Alba, Maria Jose Marcaida, Jesus Prieto, Guillermo Montoya, Rafael Molina, Marco D'Abramo
I-DmoI, from the hyperthermophilic archaeon Desulfurococcus mobilis, belongs to the LAGLIDADG homing endonuclease protein family. Its members are highly specific enzymes capable of recognizing long DNA target sequences, thus providing potential tools for genome manipulation. Working towards this particular application, many efforts have been made to generate mesophilic variants of I-DmoI that function at lower temperatures than the wild-type. Here, we report a structural and computational analysis of two I-DmoI mesophilic mutants...
November 25, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29159521/discovery-of-small-molecules-binding-to-the-normal-conformation-of-prion-by-combining-virtual-screening-and-multiple-biological-activity-evaluation-methods
#13
Lanlan Li, Wei Wei, Wen-Juan Jia, Yongchang Zhu, Yan Zhang, Jiang-Huai Chen, Jiaqi Tian, Huanxiang Liu, Yong-Xing He, Xiaojun Yao
Conformational conversion of the normal cellular prion protein, PrP(C), into the misfolded isoform, PrP(Sc), is considered to be a central event in the development of fatal neurodegenerative diseases. Stabilization of prion protein at the normal cellular form (PrP(C)) with small molecules is a rational and efficient strategy for treatment of prion related diseases. However, few compounds have been identified as potent prion inhibitors by binding to the normal conformation of prion. In this work, to rational screening of inhibitors capable of stabilizing cellular form of prion protein, multiple approaches combining docking-based virtual screening, steady-state fluorescence quenching, surface plasmon resonance and thioflavin T fluorescence assay were used to discover new compounds interrupting PrP(C) to PrP(Sc) conversion...
November 20, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29147837/development-of-saap3d-force-field-and-the-application-to-replica-exchange-monte-carlo-simulation-for-chignolin-and-c-peptide
#14
Michio Iwaoka, Toshiki Suzuki, Yuya Shoji, Kenichi Dedachi, Taku Shimosato, Toshiya Minezaki, Hironobu Hojo, Hiroyuki Onuki, Hiroshi Hirota
Single amino acid potential (SAAP) would be a prominent factor to determine peptide conformations. To prove this hypothesis, we previously developed SAAP force field for molecular simulation of polypeptides. In this study, the force field was renovated to SAAP3D force field by applying more accurate three-dimensional main-chain parameters, instead of the original two-dimensional ones, for the amino acids having a long side-chain. To demonstrate effectiveness of the SAAP3D force field, replica-exchange Monte Carlo (REMC) simulation was performed for two benchmark short peptides, chignolin (H-GYDPETGTWG-OH) and C-peptide (CHO-AETAAAKFLRAHA-NH2)...
November 17, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29134431/impact-of-domain-knowledge-on-blinded-predictions-of-binding-energies-by-alchemical-free-energy-calculations
#15
Antonia S J S Mey, Jordi Juárez Jiménez, Julien Michel
The Drug Design Data Resource (D3R) consortium organises blinded challenges to address the latest advances in computational methods for ligand pose prediction, affinity ranking, and free energy calculations. Within the context of the second D3R Grand Challenge several blinded binding free energies predictions were made for two congeneric series of Farsenoid X Receptor (FXR) inhibitors with a semi-automated alchemical free energy calculation workflow featuring FESetup and SOMD software tools. Reasonable performance was observed in retrospective analyses of literature datasets...
November 13, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29134430/modern-drug-design-the-implication-of-using-artificial-neuronal-networks-and-multiple-molecular-dynamic-simulations
#16
Oleksandr Yakovenko, Steven J M Jones
We report the implementation of molecular modeling approaches developed as a part of the 2016 Grand Challenge 2, the blinded competition of computer aided drug design technologies held by the D3R Drug Design Data Resource ( https://drugdesigndata.org/ ). The challenge was focused on the ligands of the farnesoid X receptor (FXR), a highly flexible nuclear receptor of the cholesterol derivative chenodeoxycholic acid. FXR is considered an important therapeutic target for metabolic, inflammatory, bowel and obesity related diseases (Expert Opin Drug Metab Toxicol 4:523-532, 2015), but in the context of this competition it is also interesting due to the significant ligand-induced conformational changes displayed by the protein...
November 13, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29127582/lessons-learned-from-participating-in-d3r-2016-grand-challenge-2-compounds-targeting-the-farnesoid-x-receptor
#17
Rui Duan, Xianjin Xu, Xiaoqin Zou
D3R 2016 Grand Challenge 2 focused on predictions of binding modes and affinities for 102 compounds against the farnesoid X receptor (FXR). In this challenge, two distinct methods, a docking-based method and a template-based method, were employed by our team for the binding mode prediction. For the new template-based method, 3D ligand similarities were calculated for each query compound against the ligands in the co-crystal structures of FXR available in Protein Data Bank. The binding mode was predicted based on the co-crystal protein structure containing the ligand with the best ligand similarity score against the query compound...
November 10, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29127581/lessons-learned-in-induced-fit-docking-and-metadynamics-in-the-drug-design-data-resource-grand-challenge-2
#18
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...
November 10, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29119352/using-physics-based-pose-predictions-and-free-energy-perturbation-calculations-to-predict-binding-poses-and-relative-binding-affinities-for-fxr-ligands-in-the-d3r-grand-challenge-2
#19
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...
November 8, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29101520/protein-ligand-docking-using-fft-based-sampling-d3r-case-study
#20
Dzmitry Padhorny, David R Hall, Hanieh Mirzaei, Artem B Mamonov, Mohammad Moghadasi, Andrey Alekseenko, Dmitri Beglov, Dima Kozakov
Fast Fourier transform (FFT) based approaches have been successful in application to modeling of relatively rigid protein-protein complexes. Recently, we have been able to adapt the FFT methodology to treatment of flexible protein-peptide interactions. Here, we report our latest attempt to expand the capabilities of the FFT approach to treatment of flexible protein-ligand interactions in application to the D3R PL-2016-1 challenge. Based on the D3R assessment, our FFT approach in conjunction with Monte Carlo minimization off-grid refinement was among the top performing methods in the challenge...
November 3, 2017: Journal of Computer-aided Molecular Design
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