Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Recently, our research group has proposed the hydroxyfurazanyl (4-hydroxy-1,2,5-oxadiazole-3-yl) moiety as a new non-classical isoster of the carboxy function in the design of gamma-aminobutyric acid (GABA) analogues. Some compounds showed significant activity at the GABA(A) receptor, representing the only examples of pentatomic heterocycles bearing an omega-aminoalkyl flexible side chain in the position vicinal to the hydroxy group displaying agonist activity at this receptor subtype. In this work, an ab initio analysis of the structural and electronic features of furazan-3-ol is presented, in order to provide a theoretical basis to the claimed bioisosterism with the carboxy function. An ab initio conformational study with the C-PCM implicit solvent model was carried out to elucidate the reasons of the peculiar behaviour of the furazan models. Alongside, another conformational search through molecular dynamics in explicit solvent was accomplished, in order to validate the first method. The electronic features of the 4-hydroxy-1,2,5-oxadiazole-3-yl substructure seem to account for a marked stabilising effect of the putative bioactive conformation at the GABA(A) receptor subtype. The 1,2,5-thiadiazole analogue, which shares the same conformational preference of its oxygenated counterpart, was identified as a potential candidate for synthesis and pharmacological testing. Figure 4-(omega-aminoalkyl)-1,2,5-oxadiazole-3-ol analogues of GABA.
J Mol Model 2008 Apr
PMID:Hydroxy-1,2,5-oxadiazolyl moiety as bioisoster of the carboxy function. A computational study on gamma-aminobutyric acid (GABA) related compounds. 1824 67

Theoretical studies on the coordination stabilities, spectra and DNA-binding trend for the series of metal-varied complexes, M(IDB)Cl2 (M = Mn, Fe, Co, Ni, Cu and Zn; IDB = N, N-bis(2-benzimidazolylmethyl) amine), have been carried out by using the DFT/B3LYP method and PCM model. The calculated coordination stabilities (S) for these complexes present a trend of S(Ni) > S(Co) > S(Fe) > S(Cu) > S(Zn) > S(Mn). It has been estimated from the molecular orbital energies of the complexes that the DNA-binding affinities (A) of the complexes are in the order of A(Zn) < A(Mn) < A(Fe) approximately A(Co) < A(Ni) < A(Cu). The studied results indicate that the Cu, Ni and Co complexes with large coordination stabilities present the low virtual orbitals, consequently yielding to the favorable DNA-binding affinities. The spectral properties of excitation energies and oscillator strengths for M(IDB)Cl2 in the ultraviolet region were calculated by TD-DFT/B3LYP method.
J Mol Model 2009 May
PMID:Systematic characterization on electronic structures and spectra for a series of complexes, M(IDB)Cl2 (M = Mn, Fe, Co, Ni, Cu and Zn): a theoretical study. 1908 29

Solvent impact on the structural index of aromaticity was modelled by polarised continuum field approximation (IEFPCM) and hybrid quantum chemistry (QM/MM) method. Significant solvent related relaxation of the solutes geometries were noticed especially for highly polar species. The significant reduction of the aromaticity was observed for some aromatic compounds in water solution compared to gas phase. The rationale of this fact was provided based on dipole moment changes, energy penalty for polarisation of solute and the distribution of frontier orbital densities. The incoherent predictions of explicit and implicit solvation models are noticed since in some cases the PCM approach artificially exaggerate the geometry relaxation in solution which is not observed if explicit solvent molecules are taken into account.
J Mol Model 2009 Jun
PMID:Solvent impact on the aromaticity of benzene analogues: implicit versus explicit solvent approach. 1913 15

Cyclic peptides are therapeutically attractive due to their high bioavailability, potential selectivity, and scaffold novelty. Furthermore, the presence of D-residues induces conformational preferences not followed by peptides consisting of naturally abundant L-residues. Therefore, comprehending how amino acids induce turns in peptides, subsequently facilitating cyclization, is significant in peptide design. Here, we performed 20-ns explicit-solvent molecular dynamics simulations for three diastereomeric peptides with stereochemistries: LLLLL, LLLDL, and LDLDL. Experimentally LLLLL and LDLDL readily cyclize, whereas LLLDL cyclizes in low yield. Simulations at 310 K produced conformations with inter-terminal hydrogen bonds that correlated qualitatively with the experimental cyclization trend. Energies obtained for representative structures from quantum chemical (B3LYP/PCM/cc-pVTZ//HF/6-31G*) calculations predicted pseudo-cyclic and extended conformations as the most stable for LLLLL and LLLDL, respectively, in agreement with the experimental data. In contrast, the most stable conformer predicted for peptide LDLDL was not a pseudo-cyclic structure. Moreover, D-residues preferred the experimentally less populated alpha(L) rotamers even when simulations were performed at a higher temperature and with strategically selected starting conformations. Energies calculated with molecular mechanics were consistent only with peptide LLLLL. Thus, the conformational preferences obtained for the all L: -amino acid peptide were in agreement with the experimental observations. Moreover, refinement of the force field is expected to provide far-reaching conformational sampling of peptides containing D-residues to further develop force field-based conformational-searching methods.
J Comput Aided Mol Des 2009 Sep
PMID:Modeling of peptides containing D-amino acids: implications on cyclization. 1959 48

This work presents a quantitative structure-property relationship (QSPR)-based approach allowing an accurate prediction of the excited-state properties of organic dyes (anthraquinones and azobenzenes) from ground-state molecular descriptors, obtained within the (conceptual) density functional theory (DFT) framework. The ab initio computation of the descriptors was achieved at several levels of theory, so that the influence of the basis set size as well as of the modeling of environmental effects could be statistically quantified. It turns out that, for the entire data set, a statistically-robust four-variable multiple linear regression based on PCM-PBE0/6-31G calculations delivers a R(adj)(2) of 0.93 associated to predictive errors allowing for rapid and efficient dye design. All the selected descriptors are independent of the dye's family, an advantage over previously designed QSPR schemes. On top of that, the obtained accuracy is comparable to the one of the today's reference methods while exceeding the one of hardness-based fittings. QSPR relationships specific to both families of dyes have also been built up. This work paves the way towards reliable and computationally affordable color design for organic dyes.
J Mol Graph Model 2010 Feb 26
PMID:Excited-state properties from ground-state DFT descriptors: A QSPR approach for dyes. 2003 73

Piroxicam (PRX) has been widely studied in an attempt to elucidate the causes and mechanisms of its side effects, mainly the photo-toxicity. In this paper fluorescence spectra in non-protic solvents and different polarities were carried out along with theoretical calculations. Preliminary potential surfaces of the keto and enol forms were obtained at AM1 level of theory providing the most stable conformers, which had their structure re-optimized through the B3LYP/CEP-31G(d,p) method. From the optimized structures, the electronic spectra were calculated using the TD-DFT method in vacuum and including the solvent effect through the PCM method and a single water molecule near PRX. A new potential surface was constructed to the enol tautomer at DFT level and the most stable conformers were submitted to the QST2 calculations. The experimental data showed that in apolar media, the solution fluorescence is raised. Based on conformational analysis for the two tautomers, keto and enol, the results indicated that the PRX-enol is the main tautomer related to the drug fluorescence, which is reinforced by the spectra results, as well as the interconvertion barrier obtained from the QST2 calculations. The results suggest that the PRX one of the enol conformers presents great possibility of involvement in the photo-toxicity mechanisms.
Spectrochim Acta A Mol Biomol Spectrosc 2010 Feb
PMID:A theoretical and spectroscopic study of conformational structures of piroxicam. 2004 1

This paper reports the results of our attempt to predict hydration free energies on the SAMPL2 blind challenge dataset. We mostly examine the effects of the solute electrostatic component on the accuracy of the predictions. The usefulness of electronic polarization in predicting hydration free energies is assessed by comparing the Electronic Polarization from Internal Continuum model and the self consistent reaction field IEF-PCM to standard non-polarizable charge models such as RESP and AM1-BCC. We also determine an optimal restraint weight for Dielectric-RESP atomic charges fitting. Statistical analysis of the results could not distinguish the methods from one another. The smallest average unsigned error obtained is 1.9 +/- 0.6 kcal/mol (95% confidence level). A class of outliers led us to investigate the importance of the solute-solvent instantaneous induction energy, a missing term in PB continuum models. We estimated values between -1.5 and -6 kcal/mol for a series of halo-benzenes which can explain why some predicted hydration energies of non-polar molecules significantly disagreed with experiment.
J Comput Aided Mol Des 2010 Apr
PMID:Predictions of hydration free energies from continuum solvent with solute polarizable models: the SAMPL2 blind challenge. 2035 93

The conformational landscape of phenylisoserine (PhIS) was studied. Trial structures were generated by allowing for all combinations of single-bond rotamers. Based on the B3LYP/aug-cc-pVDZ calculations 54 conformers were found to be stable in the gas phase. The six most stable conformers were further optimized at the B3LYP/aug-cc-pVTZ and MP2/aug-cc-pVDZ levels for which characteristic intramolecular hydrogen bond types were classified. To estimate the influence of water on PhIS conformation, the IEF-PCM/B3LYP/aug-cc-pVDZ calculations were carried out and showed 51 neutral and six zwitterionic conformers to be stable in water solution. According to DFT calculations, the conformer equilibrium in the gas phase is dominated by one conformer, whereas the MP2 calculations suggest three PhIS structures to be significantly populated. Comparison of DFT and MP2 energies of all 57 structures stable in water indicates that, in practice, one zwitterionic and one neutral conformer determine the equilibrium in water. Based on the AIM calculations, we found that for the neutral conformers in vacuum and in water, d(H...B) is linearly correlated with Laplacian at the H-bond critical point. Figure Phenylisoserine (PhIS) is an active side chain of cytotoxic Paclitaxel medicine. The conformational landscape of phenylisoserine was studied. One zwitterionic and one neutralconformer determine the equilibrium in water whereas in the gas phase the MP2 calculations suggest three PhIS structures to be significantly populated.
J Mol Model 2011 May
PMID:Phenylisoserine in the gas-phase and water: Ab initio studies on neutral and zwitterion conformers. 2062 8

Vibrational spectral measurements were made for 1,5-dimethyl-2-phenyl-4-[(pyridin-4-ylmethylene)-amino]-1,2-dihydro-pyrazol-3-one (DPPDP). Optimized geometrical structure and harmonic vibrational frequencies were computed by ab initio RHF and DFT (B-based BP86, BLYP, BPW91, B3-based B3P86, B3LYP, B3PW91 and O3-based O3LYP) methods using 6-311++G(d,p) basis set. Complete assignments of the observed spectra were proposed. The equilibrium geometries computed by all of the methods, were compared with X-ray diffraction results. The absorption spectra of the title compound were computed both in gas phase and in CH(3)CN solution using TD-B3LYP/6-311++G(d,p) and PCM-B3LYP/6-311++G(d,p) approaches and the calculated results provide a good description of positions of the two band maxima in the observed electronic spectrum.
Spectrochim Acta A Mol Biomol Spectrosc 2010 Nov
PMID:Experimental and DFT studies on the vibrational and electronic spectra of 1,5-dimethyl-2-phenyl-4-[(pyridin-4-ylmethylene)-amino]-1,2-dihydro-pyrazol-3-one. 2070 3

Quantum chemical methods have been used to study the conformational and electronic properties of sulfanilamide and derivatives with antibacterial activity. Calculations at B3LYP/6-311++G(3df,2p) level of theory predict the existence of four conformers for sulfanilamide depending on the orientation of p-amino and amide groups. Focusing on the sulfonamide moiety, amide NH(2) and SO(2) groups could exist either in an eclipsed or staggered arrangement. Gas-phase results predict the eclipsed conformer to be most stable but opposite to what has been rationalized previously, no stabilizing hydrogen bonds between those groups has been found through NBO analysis. When solvent effect is taken into account through the IEF-PCM method, staggered conformer is preferred; in fact, eclipsed conformation changed when explicit solvent molecules were included. Conformational analysis of all derivatives has shown two global minima which are specular images. Five out of the seven derivatives studied adopted a particular minimum energy conformation with very similar geometries.
J Mol Model 2011 Jun
PMID:Theoretical studies on sulfanilamide and derivatives with antibacterial activity: conformational and electronic analysis. 2082 Aug 28


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