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Journal of Chemical Information and Modeling

Na Liu, Wenfang Zhou, Yue Guo, Junmei Wang, Weitao Fu, Huiyong Sun, Dan Li, Mojie Duan, Tingjun Hou
Androgen receptor (AR) plays important roles in gene expression regulation, sexual phenotype maintenance and prostate cancer (PCa) development. The communications between the AR ligand-binding domain (LBD) and its coactivator are critical to the activation of AR. It is still unclear how the ligand binding would affect the AR-coactivator interactions. In this work, the effects of the ligand binding on the AR-coactivator communications were explored by molecular dynamics (MD) simulations. The results showed that the ligand binding regulates the residue interactions in the function site AF-2...
July 11, 2018: Journal of Chemical Information and Modeling
Matthew Kelly Matlock, Tyler B Hughes, Jayme L Dahlin, S Joshua Swamidass
Scientists rely on high-throughput screening tools to identify promising small-molecule compounds for the development of biochemical probes and drugs. This study focuses on the identification of promiscuous bioactive compounds, which are compounds that appear active in many high-throughput screening experiments against diverse targets, but are often false-positives which may not be easily developed into successful probes. These compounds can exhibit bioactivity due to nonspecific, intractable mechanisms of action and/or by interference with specific assay technology readouts...
July 10, 2018: Journal of Chemical Information and Modeling
Thomas Gaillard
Computer-aided protein-ligand binding predictions are a valuable help in drug discovery. Protein-ligand docking programs generally consist of two main components: a scoring function and a search algorithm. It is of interest to evaluate the intrinsic performance of scoring functions, independently of conformational exploration, to understand their strengths and weaknesses, and suggest improvements. The comparative assessment of scoring functions (CASF) provides such an evaluation. Here we add the AutoDock and Vina scoring functions to the CASF-2013 benchmark...
July 10, 2018: Journal of Chemical Information and Modeling
Phuc-Chau Do, Eric H Lee, Ly Thi Le
Conventional de novo drug design is time consuming, laborious, and resource intensive. In recent years, emerging in-silico approaches have been proven to be critical to accelerate the process of bringing drugs to market. Molecular dynamics (MD) simulations of single molecule and molecular complexes have been commonly applied to achieve accurate binding modes and binding energies of drug-receptor interactions. A derivative of MD, namely steered molecular dynamics (SMD), has been demonstrated as a promising tool for rational drug design...
July 5, 2018: Journal of Chemical Information and Modeling
Xin-Qiu Yao, Mohamed Faizan Momin, Donald Hamelberg
A difference contact network analysis (dCNA) method is developed for delineating allosteric mechanisms in proteins. The new method addresses limitations of conventional network analysis methods and is particularly suitable for allosteric systems undergoing large-amplitude conformational changes during function. Tests show that dCNA works well for proteins of varying sizes and functions. The design of dCNA is general enough to facilitate analyses of diverse dynamic data generated by molecular dynamics, crystallography, or nuclear magnetic resonance...
June 29, 2018: Journal of Chemical Information and Modeling
Thomas Maxwell Kaiser, Pieter B Burger, Christopher J Butch, Stephen Pelly, Dennis C Liotta
HIV resistance emerging against antiretroviral drugs represents a great threat to the continued prolongation of HIV-infected patients' lifespans. Methods capable of predicting resistance susceptibility in the development of compounds are therefore in great need. Targeting the major reverse transcription residues Y181, K103 and L100, we used the biologi-cal activities of compounds against these enzymes and the wild type reverse transcriptase to create Naïve Bayes Net-works. Through this machine learning approach, we could predict with high accuracy whether a compound would be susceptible to loss of potency due to resistance...
June 28, 2018: Journal of Chemical Information and Modeling
Ruifeng Liu, Kyle P Glover, Michael Geoffery Feasel, Anders Wallqvist
Key requirements for quantitative structure-activity relationship (QSAR) models to gain acceptance by regulatory authorities include a defined domain of applicability (DA) and appropriate measures of goodness-of-fit, robustness, and predictivity. Hence, many DA metrics have been developed over the past two decades. The most intuitive are perhaps distance-to-model metrics, which are most commonly defined in terms of the mean distance between a molecule and its k nearest training samples. Detailed evaluations have shown that the variance of predictions by an ensemble of QSAR models may serve as a DA metric and can outperform distance-to-model metrics...
June 27, 2018: Journal of Chemical Information and Modeling
Domenico Gadaleta, Serena Manganelli, Alessandra Roncaglioni, Cosimo Toma, Emilio Benfenati, Enrico Mombelli
Non-alcoholic hepatic steatosis is a worldwide epidemiological concern since it is among the most prominent hepatic diseases. Indeed, research in toxicology and epidemiology has gathered evidence that exposure to endocrine disruptors can perturb cellular homeostasis and cause this disease. Therefore, assessing the likelihood of a chemical to trigger hepatic steatosis is a matter of the utmost importance. However, systematic in vivo testing of all the chemicals humans are exposed to is not feasible for ethical and economical reasons...
June 27, 2018: Journal of Chemical Information and Modeling
Shao-Yu Lu, Sukrit Mukhopadhyay, Robert D J Froese, Paul M Zimmerman
The alignment of energy levels within an OLED device is paramount for high efficiency performance. In this study, the emissive, electron transport, and hole transport layers are consecutively evolved under the constraint of fixed electrode potentials. This materials development strategy takes into consideration the full multi-layer OLED device, rather than just individual components. In addition to introducing this protocol, an evolutionary method, a genetic algorithm (GA), is evaluated in detail to increase its efficiency in searching through a library of 30 million organic compounds...
June 27, 2018: Journal of Chemical Information and Modeling
Yandong Huang, Robert Harris, Jana Shen
Solution pH plays an important role in structure and dynamics of biomolecular systems; however, pH effects cannot be accurately accounted for in conventional molecular dynamics simulations based on fixed protonation states. Continuous constant pH molecular dynamics (CpHMD) based on the λ-dynamics framework calculates protonation states on the fly during dynamical simulation at a specified pH condition. Here we report the CPU-based implementation of the CpHMD method based on the GBNeck2 generalized Born (GB) implicit-solvent model in the pmemd engine of the Amber molecular dynamics package...
June 27, 2018: Journal of Chemical Information and Modeling
Pablo H Palestro, Nicolas Enrique, Sofia Goicoechea, Maria L Villalba, Laureano L Sabatier, Pedro Martin, Veronica Milesi, Luis E Bruno Blanch, Luciana Gavernet
The purpose of this investigation is to contribute to the development of new anticonvulsant drugs to treat patients with refractory epilepsy. We applied a virtual screening protocol that involved the search into molecular databases of new compounds and known drugs to find small molecules that interact with the open conformation of the Nav1.2 pore. As the 3D structure of human Nav1.2 is not available, we first assembled 3D models of the target, in closed and open conformations. After the virtual screening, the resulting candidates were submitted to a second virtual filter, to find compounds with better chances of being effective for the treatment of P-glycoprotein (P-gp) mediated resistant epilepsy...
June 26, 2018: Journal of Chemical Information and Modeling
Liam Wilbraham, Enrico Berardo, Lukas Turcani, Kim E Jelfs, Martijn A Zwijnenburg
We propose a general high-throughput virtual screening approach for the optical and electronic properties of conjugated polymers. This approach makes use of the recently developed xTB family of low-computational-cost density functional tight-binding methods from Grimme and co-workers, calibrated here to (TD-)DFT data computed for a representative diverse set of (co-)polymers. Parameters drawn from the resulting calibration using a linear model can then be applied to the xTB derived results for new polymers, thus generating near DFT-quality data with orders of magnitude reduction in computational cost...
June 25, 2018: Journal of Chemical Information and Modeling
Manish Kesherwani, Kutumbarao N H V, Devadasan Velmurugan
Thiamine pyrophosphate (TPP) riboswitch is a cis-regulatory element in the non-coding region of messenger RNA (mRNA). The aptamer domain of TPP riboswitch detects the high abundance of coenzyme thiamine pyrophosphate (TPP) and modulates the gene expression for thiamine synthetic gene. The mechanistic understanding in recognition of TPP in aptamer domain and ligand-induced compactness for folding of expression platform are most important to design novel modulators. To understand the dynamic behavior of TPP riboswitch upon TPP binding, molecular dynamics simulations were performed for 400 ns in both apo and TPP bound forms of thiM riboswitch from E...
June 25, 2018: Journal of Chemical Information and Modeling
Andrea Scarpino, György G Ferenczy, György M Keserű
Increased interest in covalent drug discovery led to the development of computer programs predicting binding mode and affinity of covalent inhibitors. Here we compare the performance of six covalent docking tools, AutoDock4, CovDock, FITTED, GOLD, ICM-Pro, and MOE, for reproducing experimental binding modes in an unprecedently large and diverse set of covalent complexes. It was found that 40-60% of the top scoring ligand poses are within 2.0 Å RMSD from the experimental binding mode. This rate showed program dependent increase and achieved 50-90% when the best RMSD among the top ten scoring poses was considered...
June 22, 2018: Journal of Chemical Information and Modeling
Scott D Bembenek, Gavin Hirst, Taraneh Mirzadegan
We analyzed an extensive data set of 3000 Janssen kinase inhibitors (spanning some 40 therapeutic projects) profiled at 414 kinases in the DiscoverX KINOME scan to better understand the necessity of using such a full kinase panel versus simply profiling one's compound at a much smaller number of kinases, or mini kinase panel (MKP), to assess its selectivity. To this end, we generated a series of MKPs over a range of sizes and of varying kinase membership using Monte Carlo simulations. By defining the kinase hit index (KHI), we quantified a compound's selectivity based on the number of kinases it hits...
June 22, 2018: Journal of Chemical Information and Modeling
Johanna H Ouml Rberg, Patricia Saenz-Méndez, Leif A Eriksson
Eukaryotic Diphthine Synthase, Dph5, is a promiscuous methyltransferase that catalyzes an extraordinary N,O-tetramethylation of 2-(3-carboxy-3-aminopropyl)-L-histidine (ACP) to yield diphthine methyl ester (DTM). These are intermediates in the biosynthesis of the post-translationally modified histidine residue diphthamide, a unique and essential residue part of eukaryotic elongation factor 2 (eEF2). Herein, the promiscuity of Saccharomyces cerevisiae Dph5 has been studied with in silico approaches, including homology modeling to provide the structure of Dph5, protein-protein docking and molecular dynamics to construct the Dph5-eEF2 complex, and quantum mechanics/molecular mechanics (QM/MM) calculations to outline a plausible mechanism...
June 21, 2018: Journal of Chemical Information and Modeling
Junchao Xia, William F Flynn, Ronald M Levy
To accelerate conformation sampling of slow dynamics from receptor or ligand, we introduced flattening potentials on selected bonded and nonbonded intramolecular interactions to the binding energy distribution analysis method (BEDAM) for calculating absolute binding free energies of protein-ligand complexes using an implicit solvent model, and implemented flattening BEDAM using the asynchronous replica exchange (AsyncRE) framework for performing large scale replica exchange molecular dynamics (REMD) simulations...
June 21, 2018: Journal of Chemical Information and Modeling
Ryan W Kung, Purshotam Sharma, Stacey D Wetmore
The present work investigates the effects of the size and shape of the nitrogen containing aromatic (NCA) skeleton on the structure of DNA damaged through adduct formation at C8 of 2'-deoxyguanosine (dG), a common DNA lesion associated with chemical carcinogenesis. Specifically, density functional theory (DFT) calculations (B3LYP-D3) and molecular dynamics (MD) simulations (AMBER) are performed on seven model adducts with systematic expansion of the NCA moiety. DFT calculations reveal that the NCA moiety shape affects the structure at the nucleobase-carcinogen linkage...
June 20, 2018: Journal of Chemical Information and Modeling
Sarah Graham, Noah Leja, Heather Ann Carlson
Mixed-solvent molecular dynamics (MixMD) is a cosolvent simulation technique for identifying binding hotspots and specific favorable interactions on a protein's surface. MixMD studies have the ability to identify these biologically relevant sites by examining the occupancy of the cosolvent over the course of the simulation. However, previous MixMD analysis required a great deal of manual inspection to identify relevant sites. To address this limitation, we have developed MixMD Probeview as a plugin for the freely available, open-source version of the molecular visualization program PyMOL...
June 15, 2018: Journal of Chemical Information and Modeling
Lorena Simon-Vidal, Oihane García-Calvo, Uxue Oteo, Sonia Arrasate, Esther Lete, Nuria Sotomayor, Humbert González-Díaz
Machine Learning (ML) algorithms are gaining importance in the processing of chemical information and modelling of chemical reactivity problems. In this work, we have developed a PTML model combining Perturbation-Theory (PT) and ML algorithms for predicting the yield of a given reaction. For this purpose, we have selected Parham cyclization, which is a general and powerful tool for the synthesis of heterocyclic and carbocyclic compounds. This reaction has both structural (substitution pattern on the substrate, internal electrophile, ring size, etc...
June 13, 2018: Journal of Chemical Information and Modeling
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