In an effort to facilitate drug discovery, computational methods for facilitating the prediction of various adverse drug reactions (ADRs) have been developed. So far, attention has not been sufficiently paid to the development of methods for the prediction of serious ADRs that occur less frequently. Some of these ADRs, such as torsade de pointes (TdP), are important issues in the approval of drugs for certain diseases. Thus there is a need to develop tools for facilitating the prediction of these ADRs. This work explores the use of a statistical learning method, support vector machine (SVM), for TdP prediction. TdP involves multiple mechanisms and SVM is a method suitable for such a problem. Our SVM classification system used a set of linear solvation energy relationship (LSER) descriptors and was optimized by leave-oneout cross validation procedure. Its prediction accuracy was evaluated by using an independent set of agents and by comparison with results obtained from other commonly used classification methods using the same dataset and optimization procedure. The accuracies for the SVM prediction of TdP-causing agents and non-TdP-causing agents are 97.4 and 84.6% respectively; one is substantially improved against and the other is comparable to the results obtained by other classification methods useful for multiple-mechanism prediction problems. This indicates the potential of SVM in facilitating the prediction of TdP-causing risk of small molecules and perhaps other ADRs that involve multiple mechanisms.

Analysis of vibrational motions and thermal fluctuational dynamics is a widely used approach for studying structural, dynamic and functional properties of proteins and nucleic acids. Development of a freely accessible web server for computation of vibrational and thermal fluctuational dynamics of biomolecules is thus useful for facilitating the relevant studies. We have developed a computer program for computing vibrational normal modes and thermal fluctuational properties of proteins and nucleic acids and applied it in several studies. In our program, vibrational normal modes are computed by using modified AMBER molecular mechanics force fields, and thermal fluctuational properties are computed by means of a selfconsistent harmonic approximation method. A web version of our program, MoViES (Molecular Vibrations Evaluation Server), was set up to facilitate the use of our program to study vibrational dynamics of proteins and nucleic acids. This software was tested on selected proteins, which show that the computed normal modes and thermal fluctuational bond disruption probabilities are consistent with experimental findings and other normal mode computations. MoViES can be accessed at http://ang.cz3.nus. edu.sg/cgi-bin/prog/norm.pl.

Ab initio molecular orbital method and Monte Carlo (MC) simulation with free energy perturbation (FEP) techniques have been used to study the aza-Wittig reaction of iminophosphoranes (H3PdNH) with formaldehyde (H2CO) in the gas phase and in three different solvents: water, methanol, and tetrahydrofuran (THF). The optimized structures and thermodynamic properties of stationary points for the title reaction system in the gas phase were calculated at the MP2/6-31G** level of theory. The effects of substituents on the reactivity of iminophosphorane were discussed. This aza-Wittig reaction is more favorable for XdH and CH3 than for XdCl in the gas phase. The potential energy profiles along the minimum energy path in the gas phase and in three solvents were obtained. The solvent effects on the H3PdNH + H2CO reaction increase in the order water ≈ methanol>THF, suggesting that the protic polar solvents are more suitable for the aza-Wittig reaction.

The aza-Wittig reaction of iminophosphoranes (X3PdNH, X=H and Cl) with formaldehyde (H2CO) was investigated in gas phase and in water using ab initio MP2/6-31G** level of theory and the self-consistent reaction field theory (isodensity polarized continuum model, IPCM). In the gas phase, the aza-Wittig reaction was predicted to be a two-step process with two dipole-dipole complexes, one four-membered ring intermediate and two transition states. The potential energy profiles along the minima energy path in gas phase and in water were obtained. The solvent effects on the thermodynamic and kinetic properties of this reaction were discussed. This aza-Wittig reaction is more favorable for X=H than for X=Cl, both in the gas phase and in water

The chemical fixation of nitric oxide (NO) reacting with alkynyllithium to produce 5-methyl-3-oxide-1,2,3-oxadiazole has been investigated by using ab initio (U)MP2 and DFT/(U)B3LYP methods. The solvent effect was assessed using the combination of microsolvation model with explicit THF ligands on lithium and continuum solvent model based on the SCRF/CPCM method at the (U)-B3LYP/6-31G* level. Our results reveal that the overall reaction is stepwise and considered to include two processes. In process 1, the nitrogen atom in nitric oxide at first attacks the C1 atom in alkynyllithium to afford the intermediate 5. In process 2, after another nitric oxide reacted with the intermediate 5 to produce 8a, we found that two pathways are involved. For path 1, the O2 atom at first attacks the C2 atom to form a five-membered ring geometry, and then lithium can rotate around the N1-O1 bond, leading to the product 5-methyl-3-oxide-1,2,3-oxadiazole followed addition of water. However, for path 2, lithium atom rotates first around the N1-O1 bond, and then the product 5-methyl-3-oxide-1,2,3-oxadiazole is also generated by addition of water. Our calculations indicate that path 1 is more favorable than path 2 in the gas phase, while both of them exist possibly in THF solvent. The overall reaction is exothermic.