Luckhana Lawtrakul

Structure-activity correlation study of HIV-1 inhibitors: Electronic and molecular parameters

SummaryQuantitative structure-activity relationships (QSARs) for 40 HIV-1 inhibitors, 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine and its derivatives, were studied. Fully optimized geometries, based on the semiempirical AM1 method, were used to calculate electronic and molecular properties of all compounds. In order to examine the relation between biological activities and structural properties, multiple linear regression models were employed. A suitable QSAR model was obtained, showing not only statistical significance, but also predictive ability. The significant molecular descriptors used were atomic charges of two substituted carbon atoms in the thymine ring, hydration energies and molar refractivities of the molecules. These descriptors allowed a physical explanation of electronic and molecular properties contributing to HIV-1 inhibitory potency.

Predicting complexation thermodynamic parameters of β-cyclodextrin with chiral guests by using swarm intelligence and support vector machines.

The Particle Swarm Optimization (PSO) and Support Vector Machines (SVMs) approaches are used for predicting the thermodynamic parameters for the 1:1 inclusion complexation of chiral guests with β-cyclodextrin. A PSO is adopted for descriptor selection in the quantitative structure-property relationships (QSPR) of a dataset of 74 chiral guests due to its simplicity, speed, and consistency. The modified PSO is then combined with SVMs for its good approximating properties, to generate a QSPR model with the selected features. Linear, polynomial, and Gaussian radial basis functions are used as kernels in SVMs. All models have demonstrated an impressive performance with R2 higher than 0.8.

Molecular dynamics simulations of UC781-cyclodextrins inclusion complexes in aqueous solution.

The inclusion complexes of highly potent anti-HIV agent, UC781, with β-cyclodextrin (βCD), 2,6-dimethyl-β-cyclodextrin (MβCD), and 2-hydroxypropyl-β-cyclodextrin (HPβCD) in aqueous solution were investigated by molecular dynamics simulations. Simulations show that the phenyl ring of UC781 is trapped inside CD cavities, while the NH group of UC781 interacts with secondary hydroxyl groups at the wider rim of CDs. The different types of CDs directly affect the binding energy and the stability of the inclusion complexes. MβCD provides the most stable inclusion complex of UC781 among all CDs in this study due to the effect of methoxy groups (-OCH(3)) at C2 and C6 positions on the glucopyranose of CDs. Structure analysis of CDs and the orientation of UC781 inside CD cavities as well as the effects of aqueous solution to the inclusion complexes of UC781/CDs are discussed. Results of this study have provided an agreeable output; therefore, a reliable prediction method for other drug/CD inclusion complex formations is introduced.

Conformational Study of the HIV-1 Reverse Transcriptase Inhibitor 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)

Abstract The conformations of the HIV-1 reverse transcriptase inhibitor 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-thymine (HEPT) are calculated by semiempirical and mainly by ab initio methods in order to estimate the potential for the rotation around the carbon sulfur single bond. The results are compared to X-ray structures of HEPT associated to the HIV-1 reverse transcriptase. The NMR spectra of the compound are calculated to obtain some information about its structure in solution. The structure of HEPT in the complex is analysed to study the intermolecular interactions between the inhibitor and the surrounding protein, which determine the geometry of the inhibition complex.

Influence of Ethanol as a Co-Solvent in Cyclodextrin Inclusion Complexation: A Molecular Dynamics Study.

Molecular dynamics (MD) simulations were used to investigate the dynamics and host-guest interactions of the inclusion complexes between a potent anti-HIV agent, UC781, and three different types of cyclodextrins (CDs) including βCD, 2,6-dimethyl-βCD (MβCD), and 2-hydroxypropyl-βCD (HPβCD) in aqueous solution with ethanol (EtOH) as a co-solvent. The MD simulation results revealed that EtOH as the co-solvent and the type of cyclodextrin affected the inclusion complex formation. From this study, UC781/MβCD provided the most stable inclusion complex. The competition for the cavity of βCD between UC781 and EtOH and the ensuing occupation of βCD cavities by EtOH resulted in a weaker interaction between βCD and UC781. In HPβCD, a supramolecular complex of UC781−HPβCD−EtOH was formed. The EtOH could easily fill the residual void space of the interior of unoccupied HPβCD due to the movement of UC781. In MβCD, the strong hydrogen bond interactions between the UC781 amide group and the secondary hydroxyl groups of MβCD significantly stabilized the inclusion complex in the presence of EtOH.

Molecular Calculations on the Conformation of the HIV-1 Reverse Transcriptase Inhibitor 1-((2-Hydroxyethoxy)methyl)-6-(phenylthio)thymine (HEPT)

Summary. 1-((2-Hydroxyethoxy)methyl)-6-(phenylthio)thymine (HEPT) is an effective inhibitor of HIV-1 reverse transcriptase. Its conformations were analyzed by molecular calculations in order to gain some information about the energetical minima and the rotational barrier around the carbon-sulfur single bond. The calculated structures were compared to the results of X-ray investigations on HEPT associated with HIV-1 reverse transcriptase. The NMR spectra of HEPT were calculated to obtain information about its structure in solution. The conformation of the molecules in the complex was analyzed with respect to the intermolecular interactions between the inhibitor and the surrounding protein which determines the geometry of the inhibition complex. Docking simulations were performed to rationalize the experimentally estimated structure of HEPT in the complex.Zusammenfassung. Die Konformationen des HIV-1 Reverse Transcriptase-Inhibitors 1-((2-Hydroxyethoxy)-methyl)-6-(phenylthio)thymin (HEPT) wurden mit Hilfe von Molekülrechnungen bestimmt, um Informationen über Energieminima und die Rotationsbarriere der Kohlenstoff-Schwefel-Einfachbindung zu erhalten. Die Ergebnisse wurden mit der Kristallstruktur der Substanz im Komplex mit HIV-1 Reverse Transcriptase verglichen. Die NMR-Spektren von HEPT wurden berechnet, um Information über seine Konformation in Lösung zu erhalten. Die Struktur von HEPT im Komplex wurde in Hinblick auf die intermolekularen Kräfte, die die Geometrie des Komplexes bestimmen, analysiert. Zum Zweck der Erklärung der Struktur der Verbindung im Komplex wurden Docking-Experimente durchgeführt.

A novel prediction approach for antimalarial activities of Trimethoprim, Pyrimethamine, and Cycloguanil analogues using extremely randomized trees

Malaria is still one of the most serious diseases in tropical regions. This is due in part to the high resistance against available drugs for the inhibition of parasites, Plasmodium, the cause of the disease. New potent compounds with high clinical utility are urgently needed. In this work, we created a novel model using a regression tree to study structure-activity relationships and predict the inhibition constant, Ki of three different antimalarial analogues (Trimethoprim, Pyrimethamine, and Cycloguanil) based on their molecular descriptors. To the best of our knowledge, this work is the first attempt to study the structure-activity relationships of all three analogues combined. The most relevant descriptors and appropriate parameters of the regression tree are harvested using extremely randomized trees. These descriptors are water accessible surface area, Log of the aqueous solubility, total hydrophobic van der Waals surface area, and molecular refractivity. Out of all possible combinations of these selected parameters and descriptors, the tree with the strongest coefficient of determination is selected to be our prediction model. Predicted Ki values from the proposed model show a strong coefficient of determination, R2=0.996, to experimental Ki values. From the structure of the regression tree, compounds with high accessible surface area of all hydrophobic atoms (ASA_H) and low aqueous solubility of inhibitors (Log S) generally possess low Ki values. Our prediction model can also be utilized as a screening test for new antimalarial drug compounds which may reduce the time and expenses for new drug development. New compounds with high predicted Ki should be excluded from further drug development. It is also our inference that a threshold of ASA_H greater than 575.80 and Log S less than or equal to -4.36 is a sufficient condition for a new compound to possess a low Ki.

Structural Aspects of Non-Nucleoside HIV-1 Reverse Transcriptase Inhibition

HIV-1 Reverse transcriptase (RT) is an essential enzyme for HIV-1 replication and, therefore, it is an important target for the attack of antiviral agents. Although some products are already on the market, there is need to design new drugs, because mutation in drug interacting disease proteins decreases the efficiency of the existing drugs. Non-nucleoside RT inhibitors fill up an allosteric, mainly hydrophobic pocket in a distinct distance from the enzymes active center. X-ray crystallographic investigations on the enzyme and on enzyme complexes provide information about the structural consequences of the protein-inhibitor interaction. Applying molecular simulations the dynamic behaviour of these biomolecular systems can be obtained in order to get some insight into the molecular flexibilities and into the detailed inhibition mechanism. Amino acids which are important for the inhibition mechanism and the interaction with inhibitor molecules can be identified for further considerations with more accurate molecular calculations. QSAR studies allow the development of proper prediction models, which are used to design new drugs. Combination of molecular docking, energy minimization and MD or MC calculations with various QSAR methods will support screening methods to find new lead compounds.

A prediction approach for anti-HIV activity of HEPT compounds using random forest technique

The human immunodeficiency virus type 1 (HIV-1) is one of the deadliest viruses that affect public health worldwide. Joint United Nations Programme on HIV/AIDS (UNAIDS) and World Health Organization estimate that there are more than 15 million people infected with this HIV-1 around the world. The cure of HIV-1 and a better understanding of effective drugs are urgently needed. In this work, we study the structure–activity relationship and predict the potency of HIV-1 drug compounds. We employ the random forest technique to select relevant molecular descriptors of 132 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) compounds toward the inhibition of HIV-1 reverse transcriptase (RT). The best model yields 5 relevant descriptors with a coefficient of determination (R2) of 0.83. Our prediction model suggests that a potent HEPT compound must be a lipophilic molecule with a high value of fractional hydrophobic van der Waals surface areas.Graphical abstract

Reduced Temperature Ammonia Decomposition Using Ni/Zr-Doped Al 2 O 3 Catalyst

The development of Ni/Zr-doped Al2O3 was achieved to reduce the reaction temperatures in ammonia decomposition by doping Zr into Al2O3 framework. The Ni/Zr-doped Al2O3 exhibits higher H2 yield and NH3 conversion than Ni/γ-Al2O3 in a continuous operation. Partial doping of Zr in Al2O3 framework can increase Ni dispersion, Ni surface area and basic sites of the Ni catalyst. These effects can promote in both dehydrogenation of NH3 and recombination of nitrogen adsorbates in an NH3 decomposition mechanism. The comparison between roles of Zr as a dopant and a promoter for Ni catalyst was also discussed.Graphical Abstract