RESUMEN
The molecular structure of 2-thiouracil, 4-thiouracil and 2,4-dithiouracil was analyzed under the effect of the first and second hydration shell by using the B3LYP density functional (DFT) method, and the results were compared to those obtained for the uracil molecule. A slight difference in the water distribution appears in these molecules. On the hydration of these molecules several trends in bond lengths and atomic charges were established. The ring in uracil molecule appears easier to be deformed and adapted to different environments as compared to that when it is thio-substituted. Molecular docking calculations of 2-thiouracil against three different pathogens: Bacillus subtilis, Escherichia coli and Candida albicans were carried out. Docking calculations of 2,4-dithiouracil ligand with various targeted proteins were also performed. Different DNA: RNA hybrid microhelixes with uridine, 2-thiouridine, 4-thiouridine and 2,4-dithiouridine nucleosides were optimized in a simple model with three nucleotide base pairs. Two main types of microhelixes were analyzed in detail depending on the intramolecular H-bond of the 2'-OH group. The weaker Watson-Crick (WC) base pair formed with thio-substituted uracil than with unsubstituted ones slightly deforms the helical and backbone parameters, especially with 2,4-dithiouridine. However, the thio-substitution significantly increases the dipole moment of the A-type microhelixes, as well as the rise and propeller twist parameters.
Asunto(s)
Antiinfecciosos/química , Simulación del Acoplamiento Molecular , Tiouracilo/química , Animales , Antiinfecciosos/farmacología , Bacillus subtilis/efectos de los fármacos , Candida albicans/efectos de los fármacos , ADN/química , Escherichia coli/efectos de los fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Unión Proteica , ARN/química , Tiouracilo/farmacologíaRESUMEN
The effect of the sulphur atom on 2-thiouracil (2TU) and 2-thiouridine molecules, as compared with uracil and uridine molecules, respectively, was carried out in several environments. The predicted IR spectrum of 2TU in the isolated state was compared with that obtained for uracil molecule and with those reported experimentally in matrix isolation. Its crystal unit cell in the solid state was simulated through a tetramer form using DFT methods for the first time. The calculated Raman spectrum was compared to the experimental ones in the solid state. A linear scaling procedure was used for this task. The first hydration shell was simulated by explicit number of water molecules surrounding 2TU up to 30 and was compared with that obtained in uracil molecule. Water molecules 'distributed' around 2TU was preferred over that 'clustering', because it can better reproduce the hydration and their effects on different parameters of the molecular structure of 2TU and uracil. The total atomic charges and several calculated thermodynamic parameters were discussed. The effect of the sulphur atom on the Watson-Crick (WC) and reverse WC base pair uridine-adenosine was estimated, and the CP corrected interaction energies were calculated. 2-thiouridine has a weaker WC pair than that with uridine, although its slight higher dipole moment (µ) facilitates the interaction with the water molecules. Several helical parameters were determined.
Asunto(s)
Adenosina/química , Modelos Moleculares , Ácidos Nucleicos/química , Análisis Espectral , Azufre/química , Tiouracilo/química , Algoritmos , Emparejamiento Base , Simulación por Computador , Enlace de Hidrógeno , Modelos Teóricos , Conformación Molecular , Agua/químicaRESUMEN
The laser Raman and IR spectra of 5-chlorocytosine have been recorded and accurately assigned in the solid state using Density functional calculations (DFT) together with the linear scaling equation procedure (LSE) and the solid state simulation of the crystal unit cell through a tetramer form. These results remarkably improve those reported previously by other authors. Several new scaling equations were proposed to be used in related molecules. The six main tautomers of the biomolecule 5-chlorocytosine were determined and optimized at the MP2 and CCSD levels, using different basis sets. The relative stabilities were compared with those obtained in cytosine and their 5-halo derivatives. Several relationships between energies, geometric parameters and NBO atomic charges were established. The effect of the chlorine substitution in the fifth position was evaluated through the stability of the Watson-Crick (WC) base pair of 5-chlorodeoxycytidine with deoxyguanosine, and through their vibrational spectra.
Asunto(s)
Emparejamiento Base , Cloro/química , Simulación por Computador , Citosina/análogos & derivados , Desoxicitidina/análogos & derivados , Desoxiguanosina/química , Espectrometría Raman , Cristalización , Citosina/química , Desoxicitidina/química , Enlace de Hidrógeno , Conformación Molecular , Espectroscopía Infrarroja por Transformada de Fourier , Estereoisomerismo , Termodinámica , VibraciónRESUMEN
The experimental FT-IR and FT-Raman spectra of 2,5-dichlorobenzonitrile molecule were recorded at room temperature, and the results compared with quantum chemical theoretical values using MP2 and DFT methods. Molecular geometry, vibrational wavenumbers and thermodynamic parameters were calculated. With the help of specific scaling procedures for the computed wavenumbers, the experimentally observed FTIR and FT-Raman bands were analyzed and assigned to different normal modes of the molecule. Most of the modes have wavenumbers in the expected range and the error obtained was in general very low. Several general conclusions were deduced. The NBO analysis has been done and Molecular Electrostatic Potential (MEP) has been plotted.
Asunto(s)
Electrones , Modelos Moleculares , Nitrilos/química , Teoría Cuántica , Espectrometría Raman , Electricidad Estática , Conformación Molecular , Espectroscopía Infrarroja por Transformada de Fourier , VibraciónRESUMEN
A comprehensive theoretical conformational analysis of the anti-HIV Nikavir prodrug was carried out; this prodrug has noticeable advantage over the approved drug AZT. The whole conformational parameters (χ, α, ß, γ, δ, Ï, P and νmax) were analysed as well as the NBO natural atomic charges. The calculations were carried out by means of DFT/B3LYP and ab initio MP2 methods with full relaxation of all geometrical parameters. The search located at least 67 stable structures, 4 of which were within a 1 kcal/mol electronic energy range of the global minimum. By MP2 it corresponds to the calculated values of the exocyclic torsional angles χ=-108.0°, ß=14.5°, γ=76.7° and ε=71.5°. The results obtained are in accordance to those found in related anti-HIV nucleoside analogues. Comparisons of the conformers with those determined in the common anti-HIV drug AZT were carried out. A detailed analysis of the lowest vibrations (<200 cm(-1)) in the best conformer of Nikavir was carried out. The most stable hydrated cluster of this conformer with 20 explicit water molecules was determined. Calculations in five of its 6'-derivatives were performed to identify structural trends that might correlate with the anti-HIV activity of these compounds. Ten structure-activity relationships/tendencies were established that can help for the design of new drugs. Several recommendations for this design were expressed.
Asunto(s)
Fármacos Anti-VIH/química , Organofosfonatos/química , Inhibidores de la Transcriptasa Inversa/química , Timidina/química , Zidovudina/análogos & derivados , Zidovudina/química , Enlace de Hidrógeno , Modelos Moleculares , Conformación Molecular , Profármacos/química , Teoría Cuántica , Relación Estructura-Actividad , TermodinámicaRESUMEN
FT-Raman and FT-IR studies of the biomolecule 5-fluoroorotic acid in the solid state were carried out. The unit cell found in the crystal was simulated as a tetramer form by density functional calculations. They were performed to clarify wavenumber assignments of the experimental observed bands in the spectra. Correlations with the molecule of uracil were made, and specific scale equations were employed to scale the wavenumbers of 5-fluoroorotic acid. Good reproduction of the experimental wavenumbers is obtained and the % error is very small in the majority of the bands. This fact confirms our simplified solid state model. The molecular structure was fully optimized using DFT and MP2 methods. The relative stability of both the syn and anti conformations was investigated, and the anti-form was found to be slightly more stable, by 7.49 kJ/mol at the MP2 level. The structures of all possible tautomeric forms were determined. The keto-form appeared as the most stable one. The NBO atomic charges and several thermodynamic parameters were also calculated.
Asunto(s)
Simulación por Computador , Modelos Moleculares , Ácido Orótico/análogos & derivados , Teoría Cuántica , Espectrometría Raman , Dimerización , Isomerismo , Conformación Molecular , Ácido Orótico/química , Espectroscopía Infrarroja por Transformada de Fourier , Termodinámica , VibraciónRESUMEN
FT-IR and FT-Raman spectra of 2,4-dichlorobenzonitrile at room temperature have been recorded in the regions 200-3500cm(-)(1) and 0-3400cm(-)(1), respectively. The observed vibrational bands were analyzed and assigned to different normal modes of the molecule according to the Wilson's notation. Density functional calculations were performed to support our frequency assignments. Specific scale equations deduced from the benzene molecule were employed to improve the calculated values. For the majority of the normal modes, the deviations between the corresponding experimental and scaled theoretical wavenumbers are located in the expected range. A correct characterization of each normal mode is of vital importance in the assignment of the observed bands, and the same has been successfully done by the aid of Potential Energy Distributions (PEDs) calculated separately for each normal mode of 2,4-dichlorobenzonitrile. The molecular structure was optimized and several thermodynamic parameters were determined. HOMO and LUMO orbital energy analysis were carried out.
Asunto(s)
Nitrilos/química , Modelos Moleculares , Teoría Cuántica , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría RamanRESUMEN
5-iodo-2'-deoxyuridine Nucleoside Analogue (IUdR) was the first selective antiviral nucleoside against herpes simplex virus type 1 and 2, and it was also a meaningful anticancer drug. Within a full study of this drug and its possible behaviour, previously, a comprehensive theoretical conformational analysis by MP2 and B3LYP was carried out, and all the possible stable structures were determined with full relaxation of all geometrical parameters. The search located 45 stable structures, and in all them, the whole conformational parameters ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], P, [Formula: see text]max) were analyzed as well as the NBO natural atomic charges. Comparisons of the conformers with those of the natural Nucleoside 2'-deoxythymidine (dT) were carried out, and the main differences between IUdR and dT were analyzed. The accuracy of the methods used was probed with the simulation of the X-ray crystal data by a tetramer form. Watson-Crick (WC) IUdR/dT···2'-deoxyadenosine pairs were analyzed for the first time using quantum chemical calculations, as well as the mispairing IUdR/dT···2'-deoxyguanosine. As result, it is observed that IUdR give rises to a slightly stronger WC pair and weaker mispairing than those with dT, therefore deforming slightly the DNA axis and difficulting the growth of the DNA virus and consequently, killing it.
Asunto(s)
Antivirales/química , ADN/química , Idoxuridina/química , Timidina/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Ribosa/química , Termodinámica , Uracilo/químicaRESUMEN
The IR and Raman spectra of 3,5-dichlorobenzonitrile (3,5-DCBN) molecule were recorded at room temperature and then the assignment of the observed fundamental bands were achieved by the aid of the theoretical vibrational spectral data obtained from a quantum chemical study carried out for the free molecule case. In the calculations performed to determine the molecular geometry, vibrational spectral data and thermodynamic parameters, Møller-Plesset second order perturbation theory (MP2) and hybrid Density Functional Theory (DFT) types of electronic structure methods, B3LYP and B3PW91, were used. The overestimations of the calculated harmonic wavenumbers were efficiently corrected by the aid of a specific scaling procedure. This empirical scaling process significantly increased the reliability of our assignments and analyses on the observed bands due to different vibrational normal modes of the molecule. For the majority of the normal modes, the deviations between the corresponding experimental and scaled theoretical wavenumbers have located in the expected range. A correct characterization of the normal modes is of vital importance in the assignment of the observed bands, and this was successfully done by the aid of the Potential Energy Distributions (PEDs) separately calculated for each normal mode of 3,5-DCBN.
Asunto(s)
Nitrilos/química , Modelos Moleculares , Teoría Cuántica , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría Raman , TermodinámicaRESUMEN
An accurate assignment of the IR spectrum in Ar matrix of 5-bromocytosine and of the IR and Raman spectra in the solid state was carried out. For this purpose Density functional calculations (DFTs) were performed to clarify wavenumber assignments of the experimental observed bands. The calculated values were scaled using scaling equations and they were compared with IR and Raman experimental data. Good reproduction of the experimental wavenumbers is obtained and the% error is very small in the majority of cases. In the isolated state all the tautomer forms of 5-bromocytosine were determined and optimized. The wavenumbers corresponding to C1 and C2b tautomers were identified and assigned in the IR experimental spectrum reported in Ar matrix. Our study confirms the existence of at least two tautomers, the amino-oxo and the amino-hydroxy in the isolated state. In the solid state the FT-IR and FT-Raman spectra of 5-bromocytosine in the powder form were recorded in the region 400-4000 cm(-1) and 50-3500 cm(-1), respectively. The unit cell found in the crystal was simulated as a tetramer form in three tautomers. Thus, it has been possible to assign all the 33 normal modes of vibration. The study indicates that the features, that are the characteristic of the vibrational spectra of cytosine, are retained by the spectra of 5-bromocytosine and it exists in the solid phase in the amino-oxo form.
Asunto(s)
Simulación por Computador , Citosina/análogos & derivados , Modelos Químicos , Teoría Cuántica , Espectrometría Raman , Citosina/química , Dimerización , Conformación Molecular , Espectroscopía Infrarroja por Transformada de Fourier , Estereoisomerismo , Termodinámica , VibraciónRESUMEN
A Raman and FT-IR study of the biomolecule 5-chlorouracil in the solid state was carried out. The unit cell found in the crystal was simulated as a tetramer form by density functional calculations. They were performed to clarify the assignments of the experimentally observed bands in the spectra. Calculations in the monomer form and comparisons with the experimental data in Ar matrix were also carried out. The error in the calculated frequencies was analyzed and reduced by using scaling equations and scaling factors deduced from the uracil molecule. The calculations with the B3LYP method and with the 6-31G(d,p) and 6-311+G(2d,p) basis set, appear in general to be useful, when combining with a scaling equation procedure or with the specific scale factors, for interpretation of the general features of the IR and Raman spectra. The scaled values were used in the reassignment of the IR and Raman experimental bands. Comparison of the results with those determined in uracil and 5-halogenated derivatives were performed. The substitution at 5-position of the uracil ring by a chlorine atom has a little effect on the geometric parameters.
Asunto(s)
Uracilo/análogos & derivados , Modelos Moleculares , Teoría Cuántica , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría Raman , Uracilo/químicaRESUMEN
The experimental IR and Raman spectra of 2-amino-3,5-dichlorobenzonitrile molecule were recorded, and the results compared with theoretical values. Molecular geometry, vibrational wavenumbers and thermodynamic parameters were calculated using MP2 and DFT quantum chemical methods. With the help of specific scaling procedures for the computed wavenumbers, the experimentally observed FTIR and FT-Raman bands were analyzed and assigned to different normal modes of vibrations of the molecule. Simulations in the dimer form were carried out to improve the assignment of the bands in the solid state experimental spectra. The error obtained was in general very low. Using PED's were determined the contributions of the different modes to each wavenumber. Several general conclusions were also deduced.
Asunto(s)
Nitrilos/química , Aminación , Modelos Moleculares , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría Raman , TermodinámicaRESUMEN
The Raman and IR spectra of the biomolecule 5-aminoorotic acid in the solid state were simulated by a dimer and tetramer forms, with the special interest in the interactions that involve the NH and NH(2) groups. The unit cell expected in the crystal was simulated as a tetramer form by density functional calculations. They were performed to clarify wavenumber assignments of the experimentally observed bands in the spectra. Correlations with the molecule of uracil were made, and accurate scaling procedures deduced by us were employed in the calculated wavenumbers of 5-aminoorotic acid. Good reproduction of the experimental wavenumbers is obtained and the % error is very small in the majority of cases. This fact confirms our simplified solid state model. The scaling leads to a reassignment of the IR and Raman experimental bands. The NBO atomic charges and several thermodynamic parameters were also calculated.
Asunto(s)
Simulación por Computador , Modelos Moleculares , Ácido Orótico/análogos & derivados , Teoría Cuántica , Espectrometría Raman , Vibración , Cristalografía por Rayos X , Dimerización , Conformación Molecular , Ácido Orótico/química , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Four new potential agents muscarinic (allosteric modulators) were synthesized and studied by using the B3LYP density functional method. The optimum conformation and geometry structure of these compounds were determined and analyzed. Solvent effects were considered including a variable number (1-15) of explicit water molecules surrounding the compound in order to simulate the first hydration shell, as well as using the Tomasi's polarized continuum model (PCM). A similar simultaneous analysis of the potents W84 and DUO-3O allosteric modulator of muscarinic receptors was also carried out. The effect of the hydration on the total atomic charges and several intermolecular distances of interest were also discussed. The biological activity against acetylcholine of our four synthesized bispyridinium salts was determined. Relationships/tendencies structure-activity were established. Several general conclusions were underlined.
Asunto(s)
Colinérgicos/química , Colinérgicos/síntesis química , Biología Computacional , Ftalimidas/química , Ftalimidas/síntesis química , Compuestos de Piridinio/química , Compuestos de Piridinio/síntesis química , Compuestos de Amonio Cuaternario/química , Compuestos de Amonio Cuaternario/síntesis química , Bases de Schiff/química , Bases de Schiff/síntesis química , Acetilcolina/química , Regulación Alostérica , Animales , Colinérgicos/farmacología , Femenino , Conformación Molecular , Ftalimidas/farmacología , Compuestos de Piridinio/farmacología , Compuestos de Amonio Cuaternario/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptores Muscarínicos/química , Receptores Muscarínicos/efectos de los fármacos , Bases de Schiff/farmacología , Relación Estructura-ActividadRESUMEN
A theoretical analysis of the effect of hydration on the molecular structure and energetics of the most stable conformers of the nucleoside analogue AZT (3'-azido-3'-deoxythymidine) was carried out. To simulate the first hydration shell, two models were considered, namely, the polarized continuum model (PCM) and the discrete model, including a variable number (from 1 to 13) of explicit water molecules surrounding the nucleoside. More than 200 cluster structures with water were analyzed by B3LYP and MP2 quantum chemical methods. In the isolated state, conformer I is the most stable by the B3LYP method, but by the MP2 method, conformer II is most stable. With nine water molecules, conformer II changes to conformer I, and this conformer I is the most stable with the further addition of water molecules. The CP-corrected formation and interaction energies for AZT and water molecules were determined. The effects of hydration on the total atomic charges and intermolecular distances were also investigated. Several general conclusions on hydrogen-bond network and involved energies are emphasized. The computed values were in good agreement with previous results for other nucleosides.
Asunto(s)
Fármacos Anti-VIH/química , Simulación por Computador , Agua/química , Zidovudina/química , Enlace de Hidrógeno , Modelos Teóricos , Estructura Molecular , Teoría Cuántica , TermodinámicaRESUMEN
A comparative theoretical conformational analysis of the tautomerism of the four most stable conformers of the antiviral analogue D4T (stavudine) and natural thymidine (Thy) nucleosides was carried out, by using the B3LYP and MP2 quantum chemical methods. The calculated structure data and energy values of the tautomers were compared with the T1 keto form and with the results determined for the thymine molecule. For each conformer, only two stable enol forms, T3 and T5, were obtained when considering different positions of hydrogen around the base. Tautomer T3 always appears more stable than T5, and more stable in the natural nucleoside Thy than in thymine or in D4T.The effect of water on the tautomers was estimated by using an explicit number of up to five water molecules to surround the nucleoside, and also by Tomasi's polarized continuum model (PCM). A total of about 200 clusters were optimised and the geometrical parameters and energies discussed. The water net differs in the three tautomers of D4T and Thy. Depending on the nature of the tautomers, cyclic, distributed water molecules, or clustered structures are formed. The deformation and interaction counterpoise (CP)-corrected energies between the nucleoside and water molecules were determined. The relative stabilities of all tautomers were established. The microhydrated environment stabilizes remarkably the enol forms more than the canonical keto one, although this one continues being the most stable. The changes in the intramolecular H-bondings and in the total atomic charges were discussed. Intramolecular H-bonds being stronger in D4T than in Thy could indicate a higher molecular flexibility for Thy.
Asunto(s)
Antivirales/química , Estavudina/química , Timidina/química , Agua/química , Enlace de Hidrógeno , Teoría Cuántica , TermodinámicaRESUMEN
The effects on the geometry structure, atomic charges and vibrational wavenumbers of the main different substituents in the 5th position of the uracil ring were analysed, and relationships were established. The 5-monosubstituted derivatives studied were 5-XU (X=F, Cl, Br, I, CH(3), NH(2), NO(2)). The geometry and vibrational wavenumbers were determined in these molecules. The FT-IR and Raman spectra were studied with the support of B3LYP calculations using several basis sets. Several general conclusions were underlined.
Asunto(s)
Uracilo/análogos & derivados , Uracilo/química , Conformación Molecular , Espectrofotometría Infrarroja , Espectrometría Raman , VibraciónRESUMEN
Geometry, vibrational wavenumbers and several thermodynamic parameters were calculated using ab initio quantum chemical methods for the 3,5-difluorobenzonitrile molecule. The results were compared with the experimental values. With the help of three specific scaling procedures, the observed vibrational wavenumbers in FTIR and Raman spectra were analysed and assigned to different normal modes of the molecule. Most of the modes have wavenumbers in the expected range and the error obtained was in general very low. Using PEDs the contributions were determined for the different modes to each wavenumber. From the PED, it is apparent that the frequency corresponding to C[triple bond]N stretching contains 87% contribution from the C[triple bond]N stretching force constant and it mixes with the C-CN stretching mode 13 to the extent of 12%. Other general conclusions were also deduced.
Asunto(s)
Flúor/química , Nitrilos/química , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría RamanRESUMEN
Geometry, vibrational frequencies, atomic charges and several thermodynamic parameters (the total energy, the zero point energy, the rotational constants and the room temperature entropy) were calculated using ab initio quantum chemical methods for 2,3-difluorobenzonitrile molecule. The results were compared with experimental values. With the help of two specific scaling procedures, observed FTIR and Raman vibrational frequencies were analysed and assigned to different normal modes of the molecule. The error obtained was in general very low. Other general conclusions have also been deduced.