Numerous methods are available for use as part of a virtual screening strategy but, as yet, no single method is able to guarantee
both a level of confidence comparable to experimental screening and a level of computing efficiency that could drastically
cut the costs of early phase drug discovery campaigns. Here, we present VSM-G (virtual screening manager for computational
grids), a virtual screening platform that combines several structure-based drug design tools. VSM-G aims to be as user-friendly
as possible while retaining enough flexibility to accommodate other in silico techniques as they are developed. In order to
illustrate VSM-G concepts, we present a proof-of-concept study of a fast geometrical matching method based on spherical harmonics
expansions surfaces. This technique is implemented in VSM-G as the first module of a multiple-step sequence tailored for high-throughput
experiments. We show that, using this protocol, notable enrichment of the input molecular database can be achieved against
a specific target, here the liver-X nuclear receptor. The benefits, limitations and applicability of the VSM-G approach are
discussed. Possible improvements of both the geometrical matching technique and its implementation within VSM-G are suggested.
Figure Basic principle of the virtual screening funnel process.
Determination of electrophilic and nucleophilic sites of a molecule is the primary task to find the active sites of the lead molecule. In the present study, the active sites of busulfan have been predicted by molecular electrostatic potential surface and Fukui function analysis with the help of dispersion corrected density functional theory. Similarly, the identification of active binding sites of the proteins against lead compound plays a vital role in the field of drug discovery. Rigid and flexible molecular docking approaches are used for this purpose. For rigid docking, Hex 8.0.0 software employing fast Fourier transform (FFT) algorithm has been used. The partial flexible blind docking simulations have been performed with AutoDock 4.2 software; where a Lamarckian genetic algorithm is employed. The results showed that the most electrophilic atoms of busulfan bind with the targets. It is clear from the docking studies that busulfan has inhibition capability toward the targets 12CA and 1BZM.
Aminophosphine oxides and aminophosphonates are, in general, very stable compounds. However, following phosphorus–carbon bond
cleavage in aqueous acidic media these compounds sometimes decompose to phosphonic acids derivatives (PIII). Despite some controversy in the literature, careful analysis supported by theoretical studies leads to the conclusion that
decomposition to PIII derivatives proceeds via an elimination reaction.
Figure The decomposition of α-aminophosphine oxides to phosphonic acid derivatives (PIII) 相似文献
Dipeptidyl peptidase IV (DPP-IV) deactivates the incretin hormones GLP-1 and GIP by cleaving the penultimate proline or alanine
from the N-terminal (P1-position) of the peptide. Inhibition of this enzyme will prevent the degradation of the incretin hormones
and maintain glucose homeostasis; this makes it an attractive target for the development of drugs for diabetes. This paper
reports 3D-QSAR analysis of several DPP-IV inhibitors, which were aligned by the receptor-based technique. The conformation
of the molecules in the active site was obtained through docking methods. The QSAR models were generated on two training sets
composed of 74 and 25 molecules which included phenylalanine, thiazolidine, and fluorinated pyrrolidine analogs. The 3D-QSAR
models are robust with statistically significant r2, q2, and values. The CoMFA and CoMSIA models were used to design some new inhibitors with several fold higher binding affinity.
Figure The CoMFA contours around molecule D1T155 (a) steric contours - favored (green); disfavored (yellow) (b) electrostatic contours
- electropositive (blue); electronegative (red) 相似文献
Inhibition of leukocyte-specific protein tyrosine kinase (Lck) activity offers one of the approaches for the treatment of
T-cell mediated inflammatory disorders including rheumatoid arthritis, transplant rejection and inflammatory bowel disease.
To explore the relationship between the structures of the N-4 Pyrimidinyl-1H-indazol-4-amines and their Lck inhibition, 3D-QSAR
study using CoMFA analysis have been performed on a dataset of 42 molecules. The bioactive conformation of the template molecule,
selected as the most potent molecule 23 from the series was obtained by performing molecular docking at the ATP binding site of Lck, which is then used to build
the rest of the molecules in the series. The constructed CoMFA model is robust with of 0.603 and conventional r2 of 0.983. The predictive power of the developed model was obtained using a test set of 10 molecules, giving predictive correlation
coefficient of 0.921. CoMFA contour analysis was performed to obtain useful information about the structural requirements
for the Lck inhibitors which could be utilized in its future design.
Figure CoMFA steric contour map. Sterically favored areas (contribution level 80%) are represented by green polyhedra. Sterically
disfavored areas (contribution level 20%) are represented by yellow polyhedra. The active molecule 23 shown in capped sticks.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
A global electrophilicity parameter and the aromaticity of some heterocyclic polyaromatic hydrocarbons were evaluated on the
basis of DFT calculations. The substitution of carbon atoms by nitrogen atoms dramatically changes the global electrophilicity
of the molecules, with the fully substituted molecule being the most electrophilic with a reactivity very close to that of
fullerene.
Figure Fully substituted heterohexabenzocoronene
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
Solanidine is the steroidal aglycon of some potato glycoalkaloids and a very important precursor for the synthesis of hormones and some pharmacologically active compounds. In this work, we make use of a new chemistry model within Density Functional Theory, called CHIH-DFT, to calculate the molecular structure of solanidine, as well to predict its infrared and ultraviolet spectra. The calculated values are compared with the experimental data available for this molecule as a means of validation of our proposed chemistry model.
Figure Molecular structure of solanidine calculated with the CHIH(small) model chemistry 相似文献
In this work, we propose a distance-based atom-type topological index (DAI) for quantitative structure-property/activity relationship (QSPR/QSAR) studies. The newly constructed index, which codes the structural environment of each atom type in a molecule, can be calculated simply. These atom-type topological indices, along with our recently proposed Lu index, were used to construct QSPR/QSAR models for several representative physical properties and biological activities of several data sets of alcohols with a range of non-hydrogen atoms by using multiple linear regression (MLR) analysis. The efficiency of these indices is verified by high quality QSPR models. The results indicate that the combined use of Lu and DAI indices promises to be a useful method for QSPR/QSAR analysis of complex compounds.
相似文献
3D-QSAR and molecular docking analysis were performed to explore the interaction of estrogen receptors (ERα and ERβ) with
a series of 3-arylquinazolinethione derivatives. Using the conformations of these compounds revealed by molecular docking,
CoMFA analysis resulted in the first quantitative structure-activity relationship (QSAR) and first quantitative structure-selectivity
relationship (QSSR) models predicting the inhibitory activity against ERβ and the selectivity against ERá. The q2 and R2 values, along with further testing, indicate that the obtained 3D-QSAR and 3D-QSSR models will be valuable in predicting
both the inhibitory activity and selectivity of 3-arylquinazolinethione derivatives for these protein targets. A set of 3D
contour plots drawn based on the 3D-QSAR and 3D-QSSR models reveal modifications of substituents at C2 and C5 of the quinazoline
which my be useful to improve both the activity and selectivity of ERβ/ ERα. Results showed that both the steric and electrostatic
factors should appropriately be taken into account in future rational design and development of more active and more selective
ERβ inhibitors for the therapeutic treatment of osteoporosis.
Figure Structures of ERβ binding with compounds 1aar, 1ax and 1aag obtained from molecular docking 相似文献
The reverse-docking of a TADDOL catalyst to rigid transition-state (TS) representations of an asymmetric hetero-Diels–Alder reaction is described. The resulting docking poses represent a simplified geometric model of the TS for the catalyzed reaction. The conformational space of the catalyst in proximity to the catalyst-free TS models is sampled stochastically and the energetically favored poses are subjected to a clustering procedure to highlight structural attributes compatible with organocatalysis. Each pose is scored and ranked based on its molecular-mechanics docking energy. The reverse-docking procedure reveals a clear energetic trend in favor of the experimentally preferred product enantiomers. Analysis of the best poses suggests a geometric model that is consistent with principles of molecular recognition, catalysis, and experimental data.
相似文献
Nitrile hydratase (NHase) is an enzyme containing non-corrin Co3+ in the non-standard active site. NHases from Pseudonocardia thermophila JCM 3095 catalyse hydration of nitriles to corresponding amides. The efficiency of the enzyme is 100 times higher for aliphatic
nitriles then aromatic ones. In order to understand better this selectivity dockings of a series of aliphatic and aromatic
nitriles and related amides into a model protein based on an X-ray structure were performed. Substantial differences in binding
modes were observed, showing better conformational freedom of aliphatic compounds. Distinct interactions with postranslationally
modified cysteines present in the active site of the enzyme were observed. Modeling shows that water molecule activated by
a metal ion may easily directly attack the docked acrylonitrile to transform this molecule into acryloamide. Thus docking
studies provide support for one of the reaction mechanisms discussed in the literature.
Figure Crystalographic structure of Pseudonocardia thermophila JCM 3095 nitrile hydratase (a) and the non-standard active site (b) 相似文献
We have used density-functional theory to investigate the neighboring-group stabilization of iodine, arsenic, and phosphorus-centered
oxyanion moieties in species such as deprotonated 2-iodoxybenzoic acid (IBX) and its analogs. The magnitudes of different
stabilizing effects and further candidates for analogous stabilization are analyzed.
相似文献
We have determined the effects that tightly bound water molecules have on the de novo design of cyclin-dependent kinase-2 (CDK2) ligands. In particular, we have analyzed the impact of a specific structural water
molecule on the chemical diversity and binding mode of ligands generated through a de novo structure-based ligand generation
method in the binding site of CDK2. The tightly bound water molecule modifies the size and shape of the binding site and we
have found that it also imposed constraints on the observed binding modes of the generated ligands. This in turn had the indirect
effect of reducing the chemical diversity of the underlying molecular scaffolds that were able to bind to the enzyme satisfactorily.
相似文献
Odorant binding proteins (OBPs) are important in insect olfactory recognition. These proteins bind specifically to insect semiochemicals and induce their seeking, mating, and alarm behaviors. Molecular docking and molecular dynamics simulations were performed to provide computational insight into the interaction mode between AgamOBP7 and novel (E)-β-farnesene (EBF) analogues with an aromatic ring. The ligand-binding cavity in OBP7 was found to be mostly hydrophobic due to the presence of several nonpolar residues. The interactions between the EBF analogues and the hydrophobic residues in the binding cavity increased in strength as the distance between them decreased. The EBF analogues with an N-methyl formamide or ester linkage had higher docking scores than those with an amide linkage. Moreover, delocalized π–π and electrostatic interactions were found to contribute significantly to the binding between the ligand benzene ring and nearby protein residues. To design new compounds with higher activity, four EBF analogues D1–D4 with a benzene ring were synthesized and evaluated based on their docking scores and binding affinities. D2, which had an N-methyl formamide group linkage, exhibited stronger binding than D1, which had an amide linkage. D4 exhibited particularly strong binding due to multiple hydrophobic interactions with the protein. This study provides crucial foundations for designing novel EBF analogues based on the OBP structure.
Transition states for selenoxide elimination have been determined for a series of Se-substituted selenocysteine (RSeCys) derivatives that have potential use in the prevention and treatment of cancer, either directly or in conjunction with cisplatin (to reduce its nephrotoxic effects). Reduced activation barriers vs R=Me and R=Ph are found when the alkyl chain length is increased or when activating groups are para to the selenide. Ortho substitution of Lewis bases stabilizes the transition state by directly donating electron density to the selenoxide. The results suggest that RSeCys derivatives incorporating the properties of glutathione peroxidase mimics will, upon oxidation, rapidly eliminate selenenic acid, a precursor to chemopreventative selenols.
Scheme Mechanism of selenoxide elimination from Se-substituted SeCys. 相似文献
The possibility that stable complexes may be formed between alpha particles (He2+) and small molecules is investigated using QCISD quantum mechanical calculations. Implications for their presence in the
terrestrial atmosphere and/or in interstellar space are discussed.
Figure Optimized structure of a stable H2OHe2+ complex 相似文献
Some important optoelectronic properties of naphtho[2,1-b:6,5-b′]difuran (DPNDF) and its two derivatives have been limelighted by applying the density functional theory (DFT). Due to their low cost, high stability and earth abundance, the DPNDF and its derivatives are considered as potential organic semiconductor materials for their optoelectronics applications. Highly proficient derivatives are obtained systematically by attaching –CN (cyanide) to DPNDF at various sites. Our calculations indicate that DPNDF has a wide and direct band gap with an energy gap of 3.157 eV. Whereas the band gaps of its derivatives are found to be decreased by 88 meV for derivative “a” and 300 meV for derivative “b” as a consequence of p orbitals present in C and N atoms in derivative structures. The narrowing of the energy gap and density of states for the derivatives of DPNDF in the present investigation suggest that energy gap can be engineered for desirable optoelectronic applications via derivatives designing. Furthermore, their obtained results for optical parameters such as the dielectric and conductivity functions, reflectivity, refractive index, and the extinction coefficients endorses their aptness for optoelectronic applications.
An automated docking procedure was used to study binding of a series of δ-selective ligands to three models of the δ-opioid
receptor. These models are thought to represent the three ligand-specific receptor conformations. Docking results are in agreement
with point mutation studies and suggest that different ligands—agonists and antagonists—may bind to the same binding site
under different receptor conformations. Docking to different receptor models (conformations) also suggests that by changing
to a receptor-specific conformation, the receptor may open or close different binding sites to other ligands.
Figure Ligands 5 (green) and 6 (orange) in bindingpocket BP1 of the R1 δ-opioid receptor model 相似文献