In the context of unknowing the experimental structure for histamine H3 receptor, which is a potential therapeutical target for numerous disorders and diseases, the theoretical methods can bring light and necessary information for a better understanding of the pharmacological implications of the aforementioned receptor. Thus, a homology model of human histamine H3 receptor was built, and SiteMap was used for the identification of potential binding sites. The top-ranked site (the putative binding site) is found in a niche surrounded by TM3, TM5, TM6, and TM7 transmembranes, and it contains the following important amino acids, Asp114 (3.32) and Trp371 (6.48), which are believed to be the key residues, responsible for ligands binding and receptor activation. The docking programs (Glide and Induced Fit) were involved and by the superposition of the best poses obtained, a structure-based protein-ligand pharmacophore model with one hydrogen bond donor, one hydrogen bond acceptor, and one positive ionic feature was developed. The PHASE software, a ligand-based method, was useful in order to validate the 3D pharmacophore hypothesis, by getting a significant Quantitative Structure Activity Relationship (QSAR) model (with R2 = 0.918 for training set and Q2 = 0.828 for test set) for the compounds taken in the study. Further, the pharmacophore model can be used in virtual screening experiments to identify new potent ligands for histamine H3 receptor.

Thirty conformers of the (3R,5S,6R)-6-acetylamidopenicillanic acid were obtained by PM3 Conformational Search performed with HyperChem7.52 software. By energy minimization with the PM3, PM6 and PM7 semiempirical MO methods included in the MOPAC12 software, thirty, eight, and nine conformers respectively were obtained. The difference Delta Delta H-f(0) between the lowest and the highest standard formation enthalpy of conformers is 7.6934 kcal.mol(-1), 3.6541 kcal.mol(-1) and 4.8064 kcal.mol(-1) for PM3, PM6, and PM7 semiempirical MO methods, respectively. For all the conformers cubic interpolation relations of functional dependence of formation enthalpy on temperature (Delta H-f(T) = a(0) + a(1)T + a(2)T(2) + a(3)T(3), T is an element of [100K,1000K]) were established: for PM3Delta H-f(T) = -153.681 (+/- 2.132) + 0.0079(+/- 0.0004)T + 1.1622(+/- 0.006)T-2.10(-4) - 3.437(+/- 0.027) T-3.10(-8); for PM6Delta H-f(T) = -179.965(+/- 1.233) + 0.008(+/- 0.001)T + 1.174(+/- 0.007)T-2.10(-4) - 3.399 (+/- 0.033) T-3.10(-8)and PM7 respectivelyDelta H-f(T) = -165.517(+/- 1.589) + 0.009(+/- 0.001)T + 1.150(+/- 0.008)T-2.10(-4) - 3.273(+/- 0.037) T-3.10(-8).The a(1), a(2) and a(3) values are neither dependent on the method of calculation, or on the conformer geometry. The a(0) free term is the only one which depends on the conformer geometry. It increases with the decreasing of the thermodynamic stability of conformers. These interpolation relations allow the calculation of molar fraction of each conformer in the mixture at a certain temperature in the interpolation range of T is an element of [100K,1000K].

Thirty conformers of (3R,5S,6R)-6-acetylamidopenicillanic acid have been obtained by using the PM3 Conformational Search implemented in the HyperChem 7.5 software. After performing the energy minimization with the PM3, PM6 and PM7 semiempirical MO methods, which are included in the MOPAC12 software, thirty, eight, and, respectively, nine conformers were obtained. The following cubic interpolation relations of functional dependence of enthalpy (Delta H), entropy (Delta S) and C-P on temperature (T is an element of[100K,1000K]) were established: for PM3: Delta H(T)=0.0613(+/- 0.0241)+0.0079(+/- 0.0004)center dot T+1.1621(+/- 0.0055)center dot 10(-4)T(2)-3.4367(+/- 0.0270)center dot 10(-8)T(3) Delta HS(T)=60.4738(+/- 1.2434)+0.2981(+/- 0.0029)center dot T-1.2594(+/- 0.0411)center dot 10(-4)T(2)+3.2563(+/- 0.1969)center dot 10(-8)T(3) C-P(T)=7.8283(+/- 0.6499)+0.2364(+/- 0.0029)center dot T-1.0955(+/- 0.4350)-10(-4)T(2)+1.2023(+/- 0.2133)center dot 10(-8)T(3) for PM6: Delta H(T)=0.0400(+/- 0.0218)+0.0089(+/- 0.0006)center dot T+1.1498(+/- 0.0082)center dot 10(-4)T(2)-3.2727(+/- 0.0367).10(-8)T(3) Delta S(T)=61.3072(+/- 1.2728)+0.3049(+/- 0.0039). T-1.3469(+/- 0.0589)center dot 10(-4)T(2)+3.7687(+/- 0.2888)center dot 10(-8)T(3) C-P(T)=9.4670(+/- 0.8905)+0.2286(+/- 0.0036)center dot T-10.0442(+/- 0.5069)center dot 10(-5)T(2)+39.8522(+/- 23.6941)center dot 10(-8)T(3) Considering the Delta G = Delta H - T center dot Delta S relation, we can state that the thermodynamic factor, which determines the variation of the conformers' biological activity, is the entropic factor, which represents the quantity of bound energy. Based on this observation, the following theorem can be stated: The dispersion of biological activities of all conformers of a flexible molecule at a temperature T is determined by their entropy.

When crystal structure solvation of a biological target is hampered by different reasons, homology modeling is a reasonable solution to overcome these impediments. Using this technique, a homology model for the human prostaglandin-E2 (PGE2) receptor subtype 3 (hEP3) was built based on the X-ray structure of the human adenosine receptor A2a (PDB ID: 3EML). The stereochemical quality of model was verified and confirmed using the PROCHECK program. For the identification of the hEP3 binding site two applications from Schrodinger suite were used: SiteMap and Glide. The docking of the endogenous ligand (PGE2) in the hEP3 binding site, highlighted the key interactions with the important amino acids of the binding site. These results were confirmed by the mutagenesis experiments published in the literature. Thus, the validated hEP3 homology model can be further used in various computational studies in order to get a better understanding of its pharmacological implications.

A series of alkyl mannofuranosides were analyzed using RM1 semi-empirical quantum chemical calculations. Cations resulted from loss of one methyl group from the alkyl chain were constructed and geometrically optimized. Their conformational analysis revealed strong interactions between mannose moiety oxygen atoms and alkyl positively charged centers, resulting in new cyclic enclosures which provide enhanced stability. Three- (oxirane), four- (oxetane), five- (1,3-dioxolane), six- (1,3-dioxane), seven- (1,3-dioxepane), eight- (1,3,6-trioxocane) and ten- (1,3,6-trioxecane) member structures were all obtained from primary or secondary carbenium ions, while the nine-member (1,3,6-trioxonane) ring remained elusive. Also, tertiary carbocations appear to avoid such stabilizations. Many cases of hydride and proton migrations, along with some chain rearrangements and decompositions were noted for branched alkyl glycoderivatives. Some energy differences could be directly calculated between stabilized (anchimerically assisted) and non-stabilized structures. These findings concern fields in which such cations are generated, like mass spectrometry analysis of side-chain glycoderivatives as well as of other oxygenated classes of compounds.

th birthday. The material starts with the description of the years spent in Bucharest between 1952 and 1966 by the brilliant student, young researcher and PhD Zeno Simon. The main topics approaches in this period by the future professor covered the theoretical calculation of some kinetic parameters for monomolecular reactions using quantum chemical methods, and the modeling of certain cellular events, as difference on self/non-self recognition. In 1966 he has returned in the city of his birth, Timisoara, where Zeno Simons versatility and scientific interest guided him through a research Institute (Institute of Chemistry Timisoara of the Romanian Academy) and two universities (the West University Timisoara and the University of Medicine and Pharmacy Timisoara), obtaining shortly, in 1979, the title of Professor and PhD tutor in chemistry. Besides the previous scientific domains, he addressed the very new research field at the time, the biological activity-molecular structure relationships, and also the application and development of quantum chemical methods. Throughout the years, in the vast majority of the cases, the Professor voluntarily gathered around him and prepared many young and enthusiastic students, researches and teachers, working together with them, creating, in time, a powerful group of computational chemistry, unique in Romania, with internationally remarkable scientific results. The large number of intensively cited papers and books, developed under the guidance of the Professor, is a testimony of the scientific viability of his group and the talent and remarkable perseverance with which was led.

Dexmedetomidine (4-[( S )-1-(2,3-dimethyl-phenyl)-ethyl]-1 H -imidazole), Dex, is potent agonist acting on α 2 -adrenergic receptors (α 2 -ARs). It can exist at the physiological pH in both forms: neutral and protonated. The results of receptor-independent and receptor-dependent studies applied to both forms of Dex are reported. A conformational analysis with PM3 semiempirical MO and ab initio HF/6-31G* methods was carried out for both forms of Dex. The calculated geometries of low-energy conformers of Dex were compared with X-ray geometry and those of conformers resulted from molecular docking of Dex in the binding pockets of 3D homology models of the α 2A -, α 2B -, and α 2C -adrenoceptor subtypes. A MM/QM (molecular mechanics/quantum mechanics) docking study was performed to refine and optimize receptor–ligand complex and close contacts between the ligand and amino acids lining the binding cavity. Two-dimensional potential energy surface and docking results suggest that the imidazole ring can easily adopt the best orientation for an efficient interaction with the carboxylate group of Asp3.32 from the binding cavity of alpha2 adrenergic receptor subtypes.

A quantitative structure - property relationship (QSPR) modeling of vapor pressure at 298.15 K, expressed as log (VP / Pa) was performed for a series of 84 hydrocarbons (63 alkanes and 21 cycloalkanes) using the van der Waals (vdW) surface area, SW/Å2, calculated by the Monte Carlo method, as the molecular descriptor. The QSPR model developed from the subset of 63 alkanes (C1-C16), deemed as the training set, was successfully used for the prediction of the log (VP / Pa) values of the 21 cycloalkanes, which was the external prediction (test) subset. A QSPR model was also developed for a series composed of all 84 hydrocarbons. Both QSPR models were statistically tested for their ability to fit the data and for prediction. The results showed that the vdW molecular surface used as molecular descriptor (MD) explains the variance of the majority of the log (VP / Pa) values in this series of 84 hydrocarbons. This MD describes very well the intermolecular forces that hold neutral molecules together. The clear physical meaning of the molecular surface values, SW/Å2, could explain the success of the QSPR models obtained with a single structural molecular descriptor.

The alpha2 adrenergic receptor ligand (S)-dexmedetomidine (4-[(S)-1-(2,3-dimethylphenyl)-ethyl]-1H-imidazole), Dex is a selective agonist with many clinical applications acting on the alpha 2 adrenergic receptor subtypes. The presence of an imidazole and a phenyl ring in molecular structure of Dex has a great importance for its potency. Both rings can contribute by their rotation to an efficient interaction with the amino acid residues from the ligand binding domain, LBD. At physiologic pH Dex can exist both in neutral and protonated ionization forms. In this paper we present results regarding conformational behavior to ring rotation, studied through ID profiles obtained with AM I, PM3 and ab initio HF/6-31G**methods. ID energy profiles for phenyl rotation have maxima of 50-2360 kcal/mol at the HF/6-31G** level, while those for rotation of imidazole ring have maxima of only 4-7 kcal/mol at T 298 K and p 1 atm. Quantum chemical studies suggest that the imidazole ring can easily rotate to adopt the best position in the LBD, while the 2,3-dimethyl ring has much more limited possibilities to rotation than the imidazole ring.

The existence and stability of alternant conjugated heterocycles six-member rings (lambda(3)-X-lambda(3)-Y)(3) (X,Y = CH,N,P,As,Sb,Bi) with elements of the 15th group was investigated using two semi-empirical MO methods: PM3 and PM6, as well as the ab initio RHF method with LACV3P**++ basis set and the DFT method with hybrid functional B3LYP/LACV3P**++. 21 heterocycles were studied, of which 12 were investigated for the first time in this paper. An analysis of the standard enthalpies of formation Delta H-f(0)(kcal/mol) calculated with PM3 and PM6, standard enthalpies Delta H-f(0)(kcal/mol) and standard free enthalpies Delta G(0)(kcal/mol) calculated with the ab initio RHF method with the LACV3P**++ basis set and the DFT/B3LYP/LACV3P**++ for 21 compounds was performed. The values of thermodynamic data for the studied hetrocycles suggest that the 6-member rings: (lambda(3)-P)(6), (lambda(3)-As)(6), (lambda(3)-Sb)(6), (lambda(3)-Bi)(6), (CH)(3)-(lambda(3)-P)(3), (lambda(3)-N-lambda(3)-P)(3), (lambda(3)-N-lambda(3)-As)(3), (lambda(3)-P-lambda(3)-Sb)(3), (lambda(3)-P-lambda(3)-Bi)(3), (lambda(3)-As-lambda(3)-Bi)(3), (lambda(3)-Sb-lambda(3)-Bi)(3) could be thermodynamically stable. Their bond lengths increase in the group, the angle X-Y-X decreases and the angle Y-X-Y increases with the increase of the atomic radius. All the studied compounds have positive standard enthalpy (Delta H-f(0) > 0) and a negative free standard enthalpy (Delta G(0) < 0), therefore these compounds have a high tendency to undergo chemical reactions.

The network was built using the basic unit [Cu(C2H3PO3)(4)center dot H2O](6-). Its geometry is best described by a distorted tetragonal pyramid: the five ligands are oriented as follows: an oxygen atom from a vinyl phosphonic group is oriented in axial position and four equatorial positions are occupied by three atoms of oxygen derived from the phosphonate group and the fourth by a water molecule. The fundamental vibration for all compounds proves that the geometries obtained by calculation are stable structures. The C=C bond lengths estimated by calculation are around 1.32 angstrom being comparable with RX experimental data. Bond lengths of Cu-O-w are underestimated compared with experimental data and other Cu-O bonds are comparable with experimental data. LUMO and HOMO energy gap is 2.933 eV for VP-3Cu and can explain the semiconductor behavior of these metal organic networks.

28 distinct conformers of the (3S,5S,6S)-6-acetylamidopenicillanic acid previously optimized at HF/STO-3G ab initio level were energetically minimized with the PM6 and PM7 semiempirical MO methods included in the MOPAC12 software. After energy minimization 14, respectively 19 distinct conformers were obtained. The difference (∆Hform(298)) between the lowest and the highest standard formation enthalpy of conformers is 4.42 kcal/mol, and 7.03 kcal/mol for PM6, and PM7 semiempirical MO methods, respectively. For the conformers obtained by the PM6 and PM7 semiempirical MO methods quadratic interpolation relations of functional dependence of formation enthalpy on temperature (∆Hform = a0 + a1T + a2T) were established. The a1 and a2 values are neither dependent on the method of calculation, nor the conformer geometry. The a0 free term is the only one which depends on the conformer geometry. It increases with the decreasing of the thermodynamic stability of conformers. These interpolation relations allow the calculation of molar fraction of each conformer in the mixture at a certain temperature in the interpolation range of 200-400K. 200 250 300 350 400 -174 -172 -170 -168 -166 -164 -162 -160 -158 -156 -154

A quantitative structure-activity relationships (QSAR) study using Multiple Linear Regression (MLR) and Partial Least Squares (PLS) methodologies was performed for a series of 127 derivatives of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), a potent inhibitor of the of the human immunodeficiency virus type 1, HIV-1 reverse transcriptase (RT). The MLR and PLS methods were employed to explore the relationship between the descriptors (as independent variables) of a pool of HEPT derivative and anti-HIV-1 activity, expressed as log (1/EC50) (as dependent variables). Using Dragon descriptors, the present study was aimed at developing a predictive and robust QSAR model for predicting anti-HIV activity of HEPT derivatives for a better understanding of the molecular features of these compounds important for their biological activity. According to the squared correlation coefficients, which had values between 0.826 and 0.809 for the MLR and PLS methods, the results demonstrated almost identical qualities and good predictive ability for both the MLR and PLS models. After dividing the dataset into training and test sets, the model predictability was tested by several parameters, including the Golbraikh-Tropsha external criteria and the goodness of fit, tested using the Y-randomization test.

A QSAR study using Multiple Linear Regression (MLR) and a Partial Least Squares (PLS) methodology was performed for a series of 127 derivatives of 1-(2-hydroxy-ethoxy)methyl]-6-(phenylthio)-timine (HEPT), a potent inhibitor of the of the human immunodeficiency virus type 1, HIV-1 reverse transcriptase (RT). To explore the relationship between a pool of HEPT derivative descriptors (as independent variables) and anti-HIV-1 activity expressed as log (1/EC50), as dependent variable) MLR and PLS methods have been employed. Using Dragon descriptors, the present study aims to develop a predictive and robust QSAR model for predicting anti-HIV activity of the HEPT derivatives for better understanding the molecular features of these compounds important for their biological activity. According to the squared correlation coefficients, which had values between 0.826 and 0.809 for the MLR and PLS methods, the results demonstrate almost identical qualities and good predictive ability for both MLR and PLS models. After dividing the dataset into training and test sets, the model predictability was tested by several parameters, including the Golbraikh-Tropsha external criteria and the goodness of fit tested with the Y-randomization test.

Results of a conformational analysis using the PM3 semiempirical MO method performed for prostaglandin E2, PGE2, the endogenous ligand of the four EP1 - EP4 receptor subtypes are reported. The PM3 conformational analysis gave around 500 conformers in a range of 5 kcal/mol and 82 conformers in a range of 3 kcal/mol above the energy of the global minimum conformer. Potential energy profiles show that flexible bonds attached to the double bonds or 1- and 2- positions of the cyclopentyl ring can be rotated in only narrow intervals. Rotating these bonds leads to only few low energy conformers that can be interconverted in other low energy conformers. The carboxyl group which is supposedly implicated in the interaction of PGE2 with the four EP receptor subtypes can be easily rotated. This group has in different conformers a large spectrum of values, suggesting that its flexibility favours the PGE2 - EP receptor interaction.

Comparative modeling of the three-dimensional structure of the human alpha(2C) adrenoceptor (alpha(2C)-AR) based on the high-resolution X-ray structure of the human beta(2)-AR (2RH1, PDB file) is reported. The sequence of the alpha(2C)-AR subtype was aligned with the sequence of the 2RH1 template and the 3D homology model of the alpha(2C)-AR was built using the Modeller software. The stereochemical quality of the 3D homology model was checked by using PROCHECK software and its accuracy was established by docking the endogen ligand, norepinephrine.

Background Research interest in phosphonates metal organic frameworks (MOF) has increased extremely in the last two decades, because of theirs fascinating and complex topology and structural flexibility. In this paper we present a mathematical model for ligand/metal ion ratio of an octahedral (O h ) network of cobalt vinylphosphonate (Co(vP)·H 2 O). Results A recurrent relationship of the ratio between the number of ligands and the number of metal ions in a lamellar octahedral (O h ) network Co(vP)·H 2 O, has been deducted by building the 3D network step by step using HyperChem 7.52 package. The mathematical relationship has been validated using X ray analysis, experimental thermogravimetric and elemental analysis data. Conclusions Based on deducted recurrence relationship, we can conclude prior to perform X ray analysis, that in the case of a thermogravimetric analysis pointing a ratio between the number of metal ions and ligands number around 1, the 3D network will have a central metal ion that corresponds to a single ligand. This relation is valid for every type of supramolecular network with divalent metal central ion O h coordinated and bring valuable information with low effort and cost.

In order to achieve the 3D homology model of the human prostaglandin E2 receptor EP4 subtype (hPE2R4) we used as template the X-rays structure (at 2.6 angstrom resolution) of the human adenosine receptor A2a (hAA2AR), (PDB file 3EML). The amino acid sequence of the PE2R4 prostanoid receptor was taken from the SWISS-PROT database (code P35408). The obtained 3D homology model was verified with the PROCHECK program in view of establishing its quality. The model was used for docking dinoprostone (prostaglandin E2), the endogenous ligand of the four PE2R subtypes.