共查询到20条相似文献,搜索用时 15 毫秒
1.
Jain AN 《Journal of computer-aided molecular design》2007,21(5):281-306
The Surflex flexible molecular docking method has been generalized and extended in two primary areas related to the search
component of docking. First, incorporation of a small-molecule force-field extends the search into Cartesian coordinates constrained
by internal ligand energetics. Whereas previous versions searched only the alignment and acyclic torsional space of the ligand,
the new approach supports dynamic ring flexibility and all-atom optimization of docked ligand poses. Second, knowledge of
well established molecular interactions between ligand fragments and a target protein can be directly exploited to guide the
search process. This offers advantages in some cases over the search strategy where ligand alignment is guided solely by a
“protomol” (a pre-computed molecular representation of an idealized ligand). Results are presented on both docking accuracy
and screening utility using multiple publicly available benchmark data sets that place Surflex’s performance in the context
of other molecular docking methods. In terms of docking accuracy, Surflex-Dock 2.1 performs as well as the best available
methods. In the area of screening utility, Surflex’s performance is extremely robust, and it is clearly superior to other
methods within the set of cases for which comparative data are available, with roughly double the screening enrichment performance. 相似文献
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Time‐Dependent Density Functional Theory (TD‐DFT) has become the most widely‐used theoretical approach to simulate the optical properties of both organic and inorganic molecules. In this contribution, we review TD‐DFT benchmarks that have been performed during the last decade. The aim is often to pinpoint the most accurate or adequate exchange‐correlation functional(s). We present both the different strategies used to assess the functionals and the main results obtained in terms of accuracy. In particular, we discuss both vertical and adiabatic benchmarks and comparisons with both experimental and theoretical reference transition energies. More specific benchmarks (oscillator strengths, excited‐state geometries, dipole moments, vibronic shapes, etc.) are summarized as well. © 2013 Wiley Periodicals, Inc. 相似文献
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Irwin JJ 《Journal of computer-aided molecular design》2008,22(3-4):193-199
Ligand enrichment among top-ranking hits is a key metric of virtual screening. To avoid bias, decoys should resemble ligands
physically, so that enrichment is not attributable to simple differences of gross features. We therefore created a directory
of useful decoys (DUD) by selecting decoys that resembled annotated ligands physically but not topologically to benchmark
docking performance. DUD has 2950 annotated ligands and 95,316 property-matched decoys for 40 targets. It is by far the largest
and most comprehensive public data set for benchmarking virtual screening programs that I am aware of. This paper outlines
several ways that DUD can be improved to provide better telemetry to investigators seeking to understand both the strengths
and the weaknesses of current docking methods. I also highlight several pitfalls for the unwary: a risk of over-optimization,
questions about chemical space, and the proper scope for using DUD. Careful attention to both the composition of benchmarks
and how they are used is essential to avoid being misled by overfitting and bias. 相似文献
5.
Ying Zhao Antonio De Nicola Toshihiro Kawakatsu Giuseppe Milano 《Journal of computational chemistry》2012,33(8):868-880
The parallel implementation of a recently developed hybrid scheme for molecular dynamics (MD) simulations (Milano and Kawakatsu, J Chem Phys 2009, 130, 214106) where self‐consistent field theory (SCF) and particle models are combined is described. Because of the peculiar formulation of the hybrid method, considering single particles interacting with density fields, the most computationally expensive part of the hybrid particle‐field MD simulation can be efficiently parallelized using a straightforward particle decomposition algorithm. Benchmarks of simulations, including comparisons of serial MD and MD‐SCF program profiles, serial MD‐SCF and parallel MD‐SCF program profiles, and parallel benchmarks compared with efficient MD program GROMACS 4.5.4 are tested and reported. The results of benchmarks indicate that the proposed parallelization scheme is very efficient and opens the way to molecular simulations of large scale systems with reasonable computational costs. © 2012 Wiley Periodicals, Inc. 相似文献
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Russian Journal of General Chemistry - Four novel pyran derivatives 1–4 are synthesized and characterized by IR, 1H NMR, HRMS, and single crystal X-ray data. Anticancer activity of the... 相似文献
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Inna Slynko Franck Da Silva Guillaume Bret Didier Rognan 《Journal of computer-aided molecular design》2016,30(9):669-683
High affinity ligands for a given target tend to share key molecular interactions with important anchoring amino acids and therefore often present quite conserved interaction patterns. This simple concept was formalized in a topological knowledge-based scoring function (GRIM) for selecting the most appropriate docking poses from previously X-rayed interaction patterns. GRIM first converts protein–ligand atomic coordinates (docking poses) into a simple 3D graph describing the corresponding interaction pattern. In a second step, proposed graphs are compared to that found from template structures in the Protein Data Bank. Last, all docking poses are rescored according to an empirical score (GRIMscore) accounting for overlap of maximum common subgraphs. Taking the opportunity of the public D3R Grand Challenge 2015, GRIM was used to rescore docking poses for 36 ligands (6 HSP90α inhibitors, 30 MAP4K4 inhibitors) prior to the release of the corresponding protein–ligand X-ray structures. When applied to the HSP90α dataset, for which many protein–ligand X-ray structures are already available, GRIM provided very high quality solutions (mean rmsd = 1.06 Å, n = 6) as top-ranked poses, and significantly outperformed a state-of-the-art scoring function. In the case of MAP4K4 inhibitors, for which preexisting 3D knowledge is scarce and chemical diversity is much larger, the accuracy of GRIM poses decays (mean rmsd = 3.18 Å, n = 30) although GRIM still outperforms an energy-based scoring function. GRIM rescoring appears to be quite robust with comparison to the other approaches competing for the same challenge (42 submissions for the HSP90 dataset, 27 for the MAP4K4 dataset) as it ranked 3rd and 2nd respectively, for the two investigated datasets. The rescoring method is quite simple to implement, independent on a docking engine, and applicable to any target for which at least one holo X-ray structure is available. 相似文献
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The excited-state energies of aza-boron-dipyrromethene (Aza-BODIPY) derivatives are investigated with Time-Dependent Density Functional Theory (TD-DFT), with twin goals. On the one hand, a pragmatic, yet efficient, computational protocol is defined in order to reach rapidly semi-quantitative estimates of the λ(max) of these challenging dyes. It turned out that a PCM-TD-BMK/6-311+G(2d,p)//PCM-PBE0/6-311G(2d,p) approach delivers appropriate lower bounds of the experimental results, despite the inherent limits of the vertical approximation. On the other hand, the method is applied to design new dyes absorbing in the near-IR. The spectral features of ca. 30 new compounds have been simulated in a systematic way, trying to efficiently combine several available synthetic strategies leading to significant bathochromic displacements. A series of dyes absorbing above 850 nm are proposed, illustrating that (relatively) fast theoretical calculations might be a useful pre-screening step preceding synthesis. 相似文献
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Virtual docking algorithms are often evaluated on their ability to separate active ligands from decoy molecules. The current state-of-the-art benchmark, the Directory of Useful Decoys (DUD), minimizes bias by including decoys from a library of synthetically feasible molecules that are physically similar yet chemically dissimilar to the active ligands. We show that by ignoring synthetic feasibility, we can compile a benchmark that is comparable to the DUD and less biased with respect to physical similarity. 相似文献
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A database consisting of 780 ligand-receptor complexes, termed SB2010, has been derived from the Protein Databank to evaluate the accuracy of docking protocols for regenerating bound ligand conformations. The goal is to provide easily accessible community resources for development of improved procedures to aid virtual screening for ligands with a wide range of flexibilities. Three core experiments using the program DOCK, which employ rigid (RGD), fixed anchor (FAD), and flexible (FLX) protocols, were used to gauge performance by several different metrics: (1) global results, (2) ligand flexibility, (3) protein family, and (4) cross-docking. Global spectrum plots of successes and failures vs rmsd reveal well-defined inflection regions, which suggest the commonly used 2 ? criteria is a reasonable choice for defining success. Across all 780 systems, success tracks with the relative difficulty of the calculations: RGD (82.3%) > FAD (78.1%) > FLX (63.8%). In general, failures due to scoring strongly outweigh those due to sampling. Subsets of SB2010 grouped by ligand flexibility (7-or-less, 8-to-15, and 15-plus rotatable bonds) reveal that success degrades linearly for FAD and FLX protocols, in contrast to RGD, which remains constant. Despite the challenges associated with FLX anchor orientation and on-the-fly flexible growth, success rates for the 7-or-less (74.5%) and, in particular, the 8-to-15 (55.2%) subset are encouraging. Poorer results for the very flexible 15-plus set (39.3%) indicate substantial room for improvement. Family-based success appears largely independent of ligand flexibility, suggesting a strong dependence on the binding site environment. For example, zinc-containing proteins are generally problematic, despite moderately flexible ligands. Finally, representative cross-docking examples, for carbonic anhydrase, thermolysin, and neuraminidase families, show the utility of family-based analysis for rapid identification of particularly good or bad docking trends, and the type of failures involved (scoring/sampling), which will likely be of interest to researchers making specific receptor choices for virtual screening. SB2010 is available for download at http://rizzolab.org . 相似文献
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In this perspective, we present an overview of recent progress on Time-Dependent Density Functional Theory (TD-DFT) with a specific focus on its accuracy and on models able to take into account environmental effects, including complex media. To this end, we first summarise recent benchmarks and define an average TD-DFT accuracy in reproducing excitation energies when a conventional approach is used. Next, coupling of TD-DFT with models able to account for different kinds of interactions between a central chromophore and nearby chemical objects (solvent, organic cage, metal as well as semi-conducting surface) is investigated. Examples of application to excitation properties are presented, allowing to briefly describe several recent computational strategies. In addition, an extension of TD-DFT to describe a phenomenon involving interacting chromophores, e.g. the electronic energy transfer (EET), is presented to illustrate that this methodology can be applied to processes beyond the vertical excitation. This perspective therefore aims to provide to non-specialists a flavour of recent trends in the field of simulations of excited states in "realistic" situations. 相似文献
14.
AC Cabrera J Klett H G Dos Santos A Perona R Gil-Redondo SM Francis EM Priego F Gago A Morreale 《Journal of chemical information and modeling》2012,52(8):2300-2309
An ultrafast docking and virtual screening program, CRDOCK, is presented that contains (1) a search engine that can use a variety of sampling methods and an initial energy evaluation function, (2) several energy minimization algorithms for fine tuning the binding poses, and (3) different scoring functions. This modularity ensures the easy configuration of custom-made protocols that can be optimized depending on the problem in hand. CRDOCK employs a precomputed library of ligand conformations that are initially generated from one-dimensional SMILES strings. Testing CRDOCK on two widely used benchmarks, the ASTEX diverse set and the Directory of Useful Decoys, yielded a success rate of ~75% in pose prediction and an average AUC of 0.66. A typical ligand can be docked, on average, in just ~13 s. Extension to a representative group of pharmacologically relevant G protein-coupled receptors that have been recently cocrystallized with some selective ligands allowed us to demonstrate the utility of this tool and also highlight some current limitations. CRDOCK is now included within VSDMIP, our integrated platform for drug discovery. 相似文献
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Scoring functions of protein–ligand interactions are widely used in computationally docking software and structure-based drug discovery. Accurate prediction of the binding energy between the protein and the ligand is the main task of the scoring function. The accuracy of a scoring function is normally evaluated by testing it on the benchmarks of protein–ligand complexes. In this work, we report the evaluation analysis of an improved version of scoring function SPecificity and Affinity (SPA). By testing on two independent benchmarks Community Structure-Activity Resource (CSAR) 2014 and Comparative Assessment of Scoring Functions (CASF) 2013, the assessment shows that SPA is relatively more accurate than other compared scoring functions in predicting the interactions between the protein and the ligand. We conclude that the inclusion of the specificity in the optimization can effectively suppress the competitive state on the funnel-like binding energy landscape, and make SPA more accurate in identifying the “native” conformation and scoring the binding decoys. The evaluation of SPA highlights the importance of binding specificity in improving the accuracy of the scoring functions. 相似文献
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Two new water soluble oxovanadium(IV) complexes with formulae Na[VO(his)(met)SO4] (1) and Na[VO(gly)(met)SO4] (2), (gly=glycine his=histidine, and met=metformin) were synthesized and characterized by LCMS, UV‐Visible absorption, infrared spectra, magnetic moment, elemental analysis, thermal analysis and electronic spectral studies. The metal center was found in an octahedral geometry. DNA binding interaction of these complexes with CT DNA has been explored by UV‐Visible absorption, fluorescence, viscosity measurements and cleavage studies. Finally the binding of the complexes with CT‐DNA could be surface binding, mainly in the groove binding. The complexes were docked in to B‐DNA sequence, 5’(D*AP*CP*CP*GP*AP*CP*GP*TP*CP*GP*GP*T)‐3’ retrieved from protein data bank (PDB ID: 423D), using Discovery Studio 2.1 software. 相似文献
18.
Mohamed A. El-Atawy Najla A. Alshaye Nada Elrubi Ezzat A. Hamed Alaa Z. Omar 《Molecules (Basel, Switzerland)》2022,27(15)
A variety of structurally different pyrimidines were synthesized. Elemental analysis, FT-IR, 1H NMR, and 13C NMR spectroscopy were used to confirm the chemical structures of all prepared compounds. The synthesized pyrimidines were screened against the growth of five human cancer cell lines (prostate carcinoma PC3, liver carcinoma HepG-2, human colon cancer HCT-116, human breast cancer MCF-7, human lung cancer A-549), and normal human lung fibroblasts (MRC-5) using MTT assay. Most of the screened pyrimidines have anti-proliferative activity on the growth of the PC3 cell line. Compounds 3b and 3d were more potent than the reference vinblastine sulfate (~2 to 3 × fold) and they can be considered promising leads for treating prostate cancer disease. Moreover, the screened compounds 3b, 3f, 3g, 3h, and 5 were assessed according to the values of their selectivity index (SI) and were found to be more selective and safer than vinblastine sulfate. Furthermore, using in silico computational tools, the physicochemical properties of all pyrimidine ligands were assessed, and the synthesized compounds fall within the criteria of RO5, thus having the potential to be orally bioavailable. 相似文献
19.
Glycosaminoglycans (GAGs) are anionic polysaccharides, which participate in key processes in the extracellular matrix by interactions
with protein targets. Due to their charged nature, accurate consideration of electrostatic and water-mediated interactions
is indispensable for understanding GAGs binding properties. However, solvent is often overlooked in molecular recognition
studies. Here we analyze the abundance of solvent in GAG-protein interfaces and investigate the challenges of adding explicit
solvent in GAG-protein docking experiments. We observe PDB GAG-protein interfaces being significantly more hydrated than protein–protein
interfaces. Furthermore, by applying molecular dynamics approaches we estimate that about half of GAG-protein interactions
are water-mediated. With a dataset of eleven GAG-protein complexes we analyze how solvent inclusion affects Autodock 3, eHiTs,
MOE and FlexX docking. We develop an approach to de novo place explicit solvent into the binding site prior to docking, which
uses the GRID program to predict positions of waters and to locate possible areas of solvent displacement upon ligand binding.
To investigate how solvent placement affects docking performance, we compare these results with those obtained by taking into
account information about the solvent position in the crystal structure. In general, we observe that inclusion of solvent
improves the results obtained with these methods. Our data show that Autodock 3 performs best, though it experiences difficulties
to quantitatively reproduce experimental data on specificity of heparin/heparan sulfate disaccharides binding to IL-8. Our
work highlights the current challenges of introducing solvent in protein-GAGs recognition studies, which is crucial for exploiting
the full potential of these molecules for rational engineering. 相似文献