| 1. |
- Brickel, Sebastian, et al.
(författare)
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Q-RepEx : A Python pipeline to increase the sampling of empirical valence bond simulations
- 2023
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Ingår i: Journal of Molecular Graphics and Modelling. - : Elsevier. - 1093-3263 .- 1873-4243. ; 119
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Tidskriftsartikel (refereegranskat)abstract
- The exploration of chemical systems occurs on complex energy landscapes. Comprehensively sampling rugged energy landscapes with many local minima is a common problem for molecular dynamics simulations. These multiple local minima trap the dynamic system, preventing efficient sampling. This is a particular challenge for large biochemical systems with many degrees of freedom. Replica exchange molecular dynamics (REMD) is an approach that accelerates the exploration of the conformational space of a system, and thus can be used to enhance the sampling of complex biomolecular processes. In parallel, the empirical valence bond (EVB) approach is a powerful approach for modeling chemical reactivity in biomolecular systems. Here, we present an open-source Python-based tool that interfaces with the Q simulation package, and increases the sampling efficiency of the EVB free energy perturbation/umbrella sampling approach by means of REMD. This approach, Q-RepEx, both decreases the computational cost of the associated REMD-EVB simulations, and opens the door to more efficient studies of biochemical reactivity in systems with significant conformational fluctuations along the chemical reaction coordinate.
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| 2. |
- Carvalho, Alexandra T P, et al.
(författare)
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Challenges in computational studies of enzyme structure, function and dynamics
- 2014
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Ingår i: Journal of Molecular Graphics and Modelling. - : Elsevier BV. - 1093-3263 .- 1873-4243. ; 54, s. 62-79
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Forskningsöversikt (refereegranskat)abstract
- In this review we give an overview of the field of Computational enzymology. We start by describing the birth of the field, with emphasis on the work of the 2013 chemistry Nobel Laureates. We then present key features of the state-of-the-art in the field, showing what theory, accompanied by experiments, has taught us so far about enzymes. We also briefly describe computational methods, such as quantum mechanics-molecular mechanics approaches, reaction coordinate treatment, and free energy simulation approaches. We finalize by discussing open questions and challenges.
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| 3. |
- Chen, Hongming, et al.
(författare)
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In silico prediction of unbound brain-to-plasma concentration ratio using machine learning algorithms
- 2011
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Ingår i: Journal of Molecular Graphics and Modelling. - : Elsevier BV. - 1093-3263 .- 1873-4243. ; 29:8, s. 985-995
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Tidskriftsartikel (refereegranskat)abstract
- Distribution over the blood-brain barrier (BBB) is an important parameter to consider for compounds that will be synthesized in a drug discovery project. Drugs that aim at targets in the central nervous system (CNS) must pass the BBB. In contrast, drugs that act peripherally are often optimised to minimize the risk of CNS side effects by restricting their potential to reach the brain. Historically, most prediction methods have focused on the total compound distribution between the blood plasma and the brain. However, recently it has been proposed that the unbound brain-to-plasma concentration ratio (K(p,uu,brain)) is more relevant. In the current study, quantitative K(p,uu,brain) prediction models have been built on a set of 173 in-house compounds by using various machine learning algorithms. The best model was shown to be reasonably predictive for the test set of 73 compounds (R(2) = 0.58). When used for qualitative prediction the model shows an accuracy of 0.85 (Kappa = 0.68). An additional external test set containing 111 marketed CNS active drugs was also classified with the model and 89% of these drugs were correctly predicted as having high brain exposure.
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| 4. |
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| 5. |
- Garcia, Juliana, et al.
(författare)
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New in silico insights into the inhibition of RNAP II by alpha-amanitin and the protective effect mediated by effective antidotes
- 2014
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Ingår i: Journal of Molecular Graphics and Modelling. - : Elsevier BV. - 1093-3263 .- 1873-4243. ; 51, s. 120-127
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Tidskriftsartikel (refereegranskat)abstract
- Poisonous alpha-amanitin-containing mushrooms are responsible for the major cases of fatalities after mushroom ingestion. alpha-Amanitin is known to inhibit the RNA polymerase II (RNAP II), although the underlying mechanisms are not fully understood. Benzylpenicillin, ceftazidime and silybin have been the most frequently used drugs in the management of alpha-amanitin poisoning, mostly based on empirical rationale. The present study provides an in silica insight into the inhibition of RNAP II by alpha-amanitin and also on the interaction of the antidotes on the active site of this enzyme. Docking and molecular dynamics (MD) simulations combined with molecular mechanics-generalized Born surface area method (MM-GBSA) were carried out to investigate the binding of alpha-amanitin and three antidotes benzylpenicillin, ceftazidime and silybin to RNAP II. Our results reveal that alpha-amanitin should affects RNAP II transcription by compromising trigger loop (TL) function. The observed direct interactions between alpha-amanitin and TL residues Leu1081, Asn1082, Thr1083, His1085 and G1y1088 alters the elongation process and thus contribute to the inhibition of RNAP II. We also present evidences that alpha-amanitin can interact directly with the bridge helix residues G1y819, Gly820 and Glu822, and indirectly with His816 and Phe815. This destabilizes the bridge helix, possibly causing RNAP II activity loss. We demonstrate that benzylpenicillin, ceftazidime and silybin are able to bind to the same site as alpha-amanitin, although not replicating the unique alpha-amanitin binding mode. They establish considerably less intermolecular interactions and the ones existing are essential confine to the bridge helix and adjacent residues. Therefore, the therapeutic effect of these antidotes does not seem to be directly related with binding to RNAP II. RNAP II alpha-amanitin binding site can be divided into specific zones with different properties providing a reliable platform for the structure-based drug design of novel antidotes for alpha-amatoxin poisoning. An ideal drug candidate should be a competitive RNAP II binder that interacts with Arg726, 11e756, Ala759, Gln760 and G1n767, but not with TL and bridge helix residues.
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| 6. |
- Genheden, Samuel
(författare)
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Effect of solvent model when probing protein dynamics with molecular dynamics
- 2017
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Ingår i: Journal of Molecular Graphics and Modelling. - : Elsevier BV. - 1093-3263 .- 1873-4243. ; 71, s. 80-87
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Tidskriftsartikel (refereegranskat)abstract
- We probe the dynamics of the Bpti and Galectin-3 proteins using molecular dynamics simulations employing three water models at different levels of resolution, viz. the atomistic TIP4P-Ewald, the coarse-grained Elba and an implicit generalised Born model. The dynamics are quantified indirectly by model-free order parameters, S2 of the backbone N-H and selected side-chain bond vectors, which also have been determined experimentally through NMR relaxation measurements. For the backbone, the order parameters produced with the three solvent models agree to a large extent with experiments, giving average unsigned deviations between 0.03 and 0.06. For the side-chains, for which the experimental data is incomplete, the deviations are considerably larger with mean deviations between 0.13 and 0.17. However, for both backbone and side-chains, it is difficult to pick a winner, as all models perform equally well overall. For a more complete set of side-chain vectors, we resort to analysing the variation among the estimates from different solvent models. Unfortunately, the variations are found to be sizeable with mean deviations between 0.11 and 0.15. Implications for computational assessment of protein dynamics are discussed.
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| 7. |
- Iribarne, F., et al.
(författare)
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Assaying phenothiazine derivatives as trypanothione reductase and glutathione reductase inhibitors by theoretical docking and Molecular Dynamics studies
- 2009
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Ingår i: Journal of Molecular Graphics and Modelling. - : Elsevier BV. - 1093-3263 .- 1873-4243. ; 28:4, s. 371-381
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Tidskriftsartikel (refereegranskat)abstract
- A theoretical docking study, conducted on a sample of previously reported phenothiazine derivatives, at the binding sites of Trypanosoma cruzi trypanothione reductase (TR) and human erythrocyte glutathione reductase (GR), examines interaction energies (affinities) towards the parasite enzyme to check for selectivity with respect to the human counterpart. Phenothiazine compounds were previously shown to be TR inhibitors. The analysis of data collected from the docking procedure was undertaken both from the numeric and graphical standpoints, including the comparison of force field, energies, molecular contacts and spatial location of the different orientations that ligands acquired at the binding sites. Molecular Dynamics simulations were also carried out for derivatives with known quantitative inhibition kinetics (Ki). The results indicate that (positively) charged phenothiazines attain larger interaction energies at TR active site, in line with previous experimental information. Suitable molecular size and shape is also needed to complement the electrostatic effect, as clearly evidenced by graphical analysis of output docked conformations. Docking energies values are reasonably well correlated with those obtained by Molecular Dynamics as well as with the experimental Ki values, confirming once again the validity of this type of scoring methods to rapidly assess ligand–receptor affinities. Alongside newly discovered classes of TR inhibitors, the promazine (N-alkylaminopropylphenothiazine) nucleus should still be considered when good candidates are sought as leaders for selective TR inhibition.
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| 8. |
- Isaksen, Geir Villy, et al.
(författare)
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Qgui : A high-throughput interface for automated setup and analysis of free energy calculations and empirical valence bond simulations in biological systems
- 2015
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Ingår i: Journal of Molecular Graphics and Modelling. - : Elsevier BV. - 1093-3263 .- 1873-4243. ; 60, s. 15-23
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Tidskriftsartikel (refereegranskat)abstract
- Structural information and activity data has increased rapidly for many protein targets during the last decades. In this paper, we present a high-throughput interface (Qgui) for automated free energy and empirical valence bond (EVB) calculations that use molecular dynamics (MD) simulations for conformational sampling. Applications to ligand binding using both the linear interaction energy (LIE) method and the free energy perturbation (FEP) technique are given using the estrogen receptor (ER alpha) as a model system. Examples of free energy profiles obtained using the EVB method for the rate-limiting step of the enzymatic reaction catalyzed by trypsin are also shown. In addition, we present calculation of high-precision Arrhenius plots to obtain the thermodynamic activation enthalpy and entropy with Qgui from running a large number of EVB simulations.
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| 9. |
- Kanan, Tarek, et al.
(författare)
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Targeting the NF-kappa B/I kappa B alpha complex via fragment-based E-Pharmacophore virtual screening and binary QSAR models
- 2019
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Ingår i: Journal of Molecular Graphics and Modelling. - : ELSEVIER SCIENCE INC. - 1093-3263 .- 1873-4243. ; 86, s. 264-277
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Tidskriftsartikel (refereegranskat)abstract
- Nuclear factor-kappa B (NF-kappa B) transcription factors represent a conserved family of proteins that regulate not only immune cells, but also heart cells, glial cells and neurons, playing a fundamental role in various cellular processes. Due to its dysregulation in certain cancer types as well as in chronic inflammation and autoimmune diseases, it has recently been appreciated as an important therapeutic target. The aim of this study was to investigate the binding pocket of NF-kappa B (p50/p65) heterodimer complex in association with NF-kappa B inhibitor I kappa B alpha to identify potent ligands via fragment-based e-pharmacophore screening. The ZINC Clean Fragments (similar to 2 million) and the Schrodingers medically relevant Glide fragments library (similar to 670) were used to create the e-pharmacophore models at the potential binding site which was validated by site mapping. Glide/HTVS docking was conducted followed by re-docking of the top 20% fragments by Glide/SP and Glide/XP protocols. The top-85000 Glide XP-docked fragments were used to generate the e-pharmacophore hypotheses. The Otava small molecule library (similar to 260000 drug-like molecules) and 85 known NF-kappa B inhibitors were additionally screened against the derived e-pharmacophore models. The top-1000 high-scored molecules, which were well aligned to the e-pharmacophore models, from the Otava small molecule library, were then docked into the binding pocket. Finally, the selected 88 hit molecules and the 85 known inhibitors were analyzed by the MetaCore/MetaDrug (TM) platform, which uses developed binary QSAR models for therapeutic activity prediction as well as pharmacokinetic and toxicity profile predictions of screening molecules. Ligand selection criteria led to the refinement of 3 potent hit molecules using molecular dynamics (MD) simulations to better investigate their structural and dynamical profiles. The selected hit molecules had a low toxicity and a significant therapeutic potential for heart failure, antiviral activity, asthma and depression, all conditions in which NF-kappa B plays a critical role. These hit ligands were also structurally stable at the NE-kappa B/I kappa B alpha complex as per the MD simulations and MM/GBSA analysis. Two of these ligands (Otava IDs: 1426436 and 6248112) showed stronger binding and therefore are hypothesized to be more potent. The identification of new potent NF-kappa B/I kappa B alpha inhibitors may thus present a novel therapy for inflammation-mediated conditions as well as cancer, facilitating more efficient research, and leading the way to future drug development efforts. (C) 2018 Elsevier Inc. All rights reserved.
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| 10. |
- Muthas, Daniel, et al.
(författare)
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Is it possible to increase hit rates in structure-based virtual screening by pharmacophore filtering? : An investigation of the advantages and pitfalls of post-filtering
- 2008
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Ingår i: Journal of Molecular Graphics and Modelling. - : Elsevier BV. - 1093-3263 .- 1873-4243. ; 26:8, s. 1237-1251
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated the influence of post-filtering virtual screening results, with pharmacophoric features generated from an X-ray structure, on enrichment rates. This was performed using three docking softwares, zdock+, Surflex and FRED, as virtual screening tools and pharmacophores generated in UNITY from co-crystallized complexes. Sets of known actives along with 9997 pharmaceutically relevant decoy compounds were docked against six chemically diverse protein targets namely CDK2, COX2, ERalpha, fXa, MMP3, and NA. To try to overcome the inherent limitations of the well-known docking problem, we generated multiple poses for each compound. The compounds were first ranked according to their scores alone and enrichment rates were calculated using only the top scoring pose of each compound. Subsequently, all poses for each compound were passed through the different pharmacophores generated from co-crystallized complexes and the enrichment factors were re-calculated based on the top-scoring passing pose of each compound. Post-filtering with a pharmacophore generated from only one X-ray complex was shown to increase enrichment rates in all investigated targets compared to docking alone. This indicates that this is a general method, which works for diverse targets and different docking softwares.
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