QSAR Evaluations to Unravel the Structural Features in Lysine-Specific Histone Demethylase 1A Inhibitors for Novel Anticancer Lead Development Supported by Molecular Docking,MD Simulation and MMGBSA

Using 84 structurally diverse and experimentally validated LSD1/KDM1A inhibitors, quantitative structure–activity relationship (QSAR) models were built by OECD requirements. In the QSAR analysis, certainly significant and understated pharmacophoric features were identified as critical for LSD1 inhibition, such as a ring Carbon atom with exactly six bonds from a Nitrogen atom, partial charges of lipophilic atoms within eight bonds from a ring Sulphur atom, a non-ring Oxygen atom exactly nine bonds from the amide Nitrogen, etc. The genetic algorithm–multi-linear regression (GA-MLR) and double cross-validation criteria were used to create robust QSAR models with high predictability. In this study, two QSAR models were developed, with fitting parameters like R² = 0.83–0.81, F = 61.22–67.96, internal validation parameters such as Q²_LOO = 0.79–0.77, Q²_LMO = 0.78–0.76, CCC_cv = 0.89–0.88, and external validation parameters such as, R2ext = 0.82 and CCCex = 0.90. In terms of mechanistic interpretation and statistical analysis, both QSAR models are well-balanced. Furthermore, utilizing the pharmacophoric features revealed by QSAR modelling, molecular docking experiments corroborated with the most active compound’s binding to the LSD1 receptor. The docking results are then refined using Molecular dynamic simulation and MMGBSA analysis. As a consequence, the findings of the study can be used to produce LSD1/KDM1A inhibitors as anticancer leads.     

A single server queue with cyclically indexed arrival and service rates

In this paper we consider a queueing model that results from at least two apparently unrelated areas. One motivation to study a system of this type results from a test case of a computer simulation factor screening technique calledfrequency domain methodology. A second motivation comes from manufacturing, where due to cyclic scheduling of upstream machines, the arrival process to downstream machines is periodic. The model is a single server queue with FIFO service discipline and exponential interarrival and service times where the arrival and/or service rates are deterministic cyclic functions of the customer sequence number. We provide steady state results for the mean number in the system for the model with cyclic arrival and fixed service rates and for the model with fixed arrival and cyclic service rates. For the model with both cyclic arrival and service rates, upper and lower bounds are developed for the steady state mean waiting time in the system. Throughout the paper various implications and/or insights derived from the results of this study are discussed for frequency domain methodology.The authors acknowledge the financial support of the CBA/GSB Faculty Research Committee of the College of Business Administration, The University of Texas at Austin.     

Syntheses of isomers of protoporphyrin-IX with permuted propionic side-chains

Total syntheses of hemins with permutations of the propionic side-chains in the C and D rings (compared with protoporphyrin-IX) are described. The products, 3, 2 and 4 , are the dimethyl esters of protoporphyrins -I, -XI, and -XIV, respectively. They are of interest in connection with nmr studies designed to elucidate the structural features of the heme crevice in myoglobin and the effect of structural modifications of the C and D rings on the kinetics of heme-apoprotein reconstitutions, as well as studies of substrate specificity of the heme degradation enzyme, heme oxygenase.     

Theoretical evaluation of sound velocities in binary liquid mixtures containing triethyl amine

The sound velocity in binary mixtures of organic liquids containing triethylamine, a weakly polar molecule as the common component, has been evaluated theoretically, based on the Free Length Theory (F.L.T.) of Jacobson and Collision Factor Theory (C.F.T.) of Schaaffs. The results are presented along with the experimental values. The two theories, applied to mixtures of triethylamine with Benzene, Cyclohexane, Dioxan, O-xylene, Toluene, Pyridine and Aniline, are compared. The theoretical values appear to be in reasonable agreement with experimental values.     

On the compensation effect

Arrhenius equation is popularly used to relate the change in the rate constant with temperature. The linearized form of Arrhenius equation has often been used to establish a relation between InA andE for a series of related reactions. Occurrence of such a compensating behavior between InA andE has been widely reported in the literature. The validity of the compensation effect has been heatedly debated. Compensation effect can arise from computational artifact or can arise from various chemical factors. This depends entirely on the data set used to establish the compensation behavior. This article stresses the importance of statistical analysis and the use of simple Arrhenius plots to draw conclusions regarding the occurrence of compensation effect. With the help of a few examples, some checkpoints to draw conclusions regarding the occurrence of true or false compensation effect are suggested.

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Zusammenfassung Die Arrhenius-Gleichung wird gewöhnlich zur Beschreibung des Zusammenhanges zwischen Geschwindigkeitskonstante und Temperatur benutzt. Die linearisierte Form der Arrhenius-Gleichung wurde dazu benutzt, eine Beziehung zwischen InA undE für eine Reihe von Reaktionen des gleichen Typs aufzustellen. Ein solches Kompensationsverhalten von InA undE wurde in der Literatur beschrieben, die Realität des Kompensationseffektes war jedoch Gegenstand heftiger Debatten. Ein Kompensationseffekt kann durch ein Rechenartefakt vorgetäuscht oder aber durch verschiedene chemische Faktoren bedingt sein. Dies hängt ausschließlich von der für den Nachweis des Kompensationsverhaltens aufgestellten Datenfolge ab. Dieser Artikel unterstreicht die Wichtigkeit der statistischen Analyse und die Verwendung einfacher Arrheniusgeraden für sich auf das Vorliegen eines Kompensationseffektes beziehende Schlußfolgerungen. An Hand einiger Beispiele werden einige Kontrollmöglichkeiten zur Unterscheidung tatsächlicher und vorgetäuschter Kompensationseffekte aufgezeigt.

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A stoichiometric approach to quantitative structure-property relationships (QSPR)

An unusual analogy between the quantitative structure-property relationships (QSPR), stoichiometry, chemical thermodynamics, and kinetics is presented. Namely, the conventional ordinary least-squares (OLS) QSPR analysis is modified so as to explicitly minimize the residuals of the species subject to a set of linear relations among the residuals. The ways the linear relations among the residuals are visualized and defined totally resemble the formalism of chemical stoichiometry and, therefore, were called isostructural reactions. It is further proved that the residuals may be uniquely partitioned into a sum of contributions associated with a set of isostructural reactions that have the same properties as the response reactions (RERs) previously deduced by us from chemical thermodynamics and kinetics. This finding is shown to be a useful tool for a deeper understanding of the QSPR. In particular, the isostructural RERs approach may be effectively used to detect the outliers.     

Theoretical studies on conformational preferences of model modified nucleic acid base N6-(N-alanylcarbonyl) adenine

Conformational preferences of model modified nucleic acid base N⁶-(N-alanylcarbonyl) adenine, ac⁶Ade, have been investigated using the quantum chemical PCILO (perturbative configuration interaction using localized orbitals) method. The multidimensional conformational space has been searched using selected grid points formed by combining the various torsion angles that take favored values derived from energy variation with respect to each torsion angle individually. The preferred molecular structure is stabilized by an intramolecular hydrogen bond from N(11)H of the amino acid to N(1) of the adenine. The observed crystal structure conformations for the naturally occurring, anticodon adjacent, threonyl analogs, tc⁶Ade, correspond to the predicted most stable conformation for the model modified base ac⁶Ade. Three stable, low energy conformations differing in the orientations of the carboxyl group and the amino acid side chain are predicted within 1 kcal/mol of the most stable structure. The possible bifurcated hydrogen bonding of N(11)H with N(1) and either of the carboxyl oxygens is of minor significance. The indicated orientational flexibility for the carboxyl group and the amino acid side chain may enable convenient probing of the molecular environment, in the vicinity of the anticodon in tRNA, by the amino acid substituent, with only modest changes in energy stabilization.     

SOME COMPONENTS OF THE TUMOR-LOCALIZING FRACTION OF HEMATOPORPHYRIN DERIVATIVE

In continuation of the effort to delineate the structure of Photofrin, a chromatographically well separated component of the tumor-localizing fraction was isolated and purified using a combination of gel filtration chromatography and semi-preparative high-performance liquid chromatography. This component, the least hydrophobic of the tumor-localizing fraction, was deemed to be dihematoporphyrin ether, based on mass spectrometric analysis and its behavior toward base hydrolysis and lithium aluminum hydride reduction. Although less potent than Photofrin, the purified component was an active photosensitizer.