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Abstract: The carbon–hydrogen bond dissociation enthalpy (BDE) concept is evaluated as a potential computed indicator of stability of pharmaceutical drug substance candidates – specifically for oxidative stability of these molecules. Computational methods are discussed. Accuracy and validity of the methods are evaluated. BDEs are computed for several well-known molecules, for which stability and degradant identification information is known. Anecdotal correlations are noted between the lowest BDE energies of familiar molecules (sertraline, ezlopitant and related structures, ziprasidone, trovafloxacin, and varenicline), the sites of oxidative lability on these molecules and the identities of oxidative degradants. A low BDE may correlate in general with a reactive site on a molecule, not just an oxidatively susceptible one. [Copyright &y& Elsevier]

Abstract: The absorption maxima, , of various organic dyes such as indigo, azobenzene, phenylamine, hydrazone, anthraquinone, naphthoquinone, and malachite green were calculated using the AM1, PM3, and PM5 semiempirical molecular orbital theories with the configuration interaction singles (CIS) and random phase approximation (RPA) approaches. The calculated were then compared with the values obtained by CNDO/S, INDO/S, ab initio CIS, and time-dependent density functional theory (TD-DFT). We found that the values calculated by AM1, PM3, and PM5 were in good correlation with the observed values. When B3LYP/cc-pVDZ optimized geometries were used, the square of the correlation coefficients between the calculated and observed , , at the AM1-RPA, PM3-RPA, and PM5-RPA levels were 0.891, 0.897, and 0.927, respectively. In particular, at PM5-RPA//B3LYP/cc-pVDZ was the largest among those obtained from all the other calculations including TD/B3LYP/cc-pVDZ//B3LYP/cc-pVDZ . Accordingly, the standard deviation of the difference between observed and calculated by the linear regression function at PM5-RPA//B3LYP/cc-pVDZ was the smallest. It was therefore concluded that this method was the most promising for the prediction of of various dyes among the computational methods studied here. When AM1 optimized geometries were used, at the AM1-RPA, PM3-RPA, and PM5-RPA levels were 0.822, 0.841, and 0.901, respectively, and they were also comparable to that at TD/B3LYP/cc-pVDZ//B3LYP/cc-pVDZ. Therefore, although some calibration efforts may be needed for AM1 geometries, PM5-RPA(CIS)//AM1 may be a second candidate available for the prediction of the absorption maxima of dyes, especially in the case of emphasizing computational cost. [Copyright &y& Elsevier]

Twenty years ago, the landmark AM1 was introduced, and has since had an increasingly wide following among chemists due to its consistently good results and time-tested reliability—being presently available in countless computational quantum chemistry programs. However, semiempirical molecular orbital models still are of limited accuracy and need to be improved if the full potential of new linear scaling techniques, such as MOZYME and LocalSCF, is to be realized. Accordingly, in this article we present RM1 (Recife Model 1): a reparameterization of AM1. As before, the properties used in the parameterization procedure were: heats of formation, dipole moments, ionization potentials and geometric variables (bond lengths and angles). Considering that the vast majority of molecules of importance to life can be assembled by using only six elements: C, H, N, O, P, and S, and that by adding the halogens we can now build most molecules of importance to pharmaceutical research, our training set consisted of 1736 molecules, representative of organic and biochemistry, containing C, H, N, O, P, S, F, Cl, Br, and I atoms. Unlike AM1, and similar to PM3, all RM1 parameters have been optimized. For enthalpies of formation, dipole moments, ionization potentials, and interatomic distances, the average errors in RM1, for the 1736 molecules, are less than those for AM1, PM3, and PM5. Indeed, the average errors in kcal · mol-1 of the enthalpies of formation for AM1, PM3, and PM5 are 11.15, 7.98, and 6.03, whereas for RM1 this value is 5.77. The errors, in Debye, of the dipole moments for AM1, PM3, PM5, and RM1 are, respectively, 0.37, 0.38, 0.50, and 0.34. Likewise, the respective errors for the ionization potentials, in eV, are 0.60, 0.55, 0.48, and 0.45, and the respective errors, in angstroms, for the interatomic distances are 0.036, 0.029, 0.037, and 0.027. The RM1 average error in bond angles of 6.82° is only slightly higher than the AM1 figure of 5.88°, and both are much smaller than the PM3 and PM5 figures of 6.98° and 9.83°, respectively. Moreover, a known error in PM3 nitrogen charges is corrected in RM1. Therefore, RM1 represents an improvement over AM1 and its similar successor PM3, and is probably very competitive with PM5, which is a somewhat different model, and not fully disclosed. RM1 possesses the same analytical construct and the same number of parameters for each atom as AM1, and, therefore, can be easily implemented in any software that already has AM1, not requiring any change in any line of code, with the sole exception of the values of the parameters themselves. © 2006 Wiley Periodicals, Inc. J Comput Chem 27: 1101–1111, 2006 [ABSTRACT FROM AUTHOR]

Abstract: In this work we report a comparative Austin method 1 (AM1), parametric method 3 (PM3), and parametric method 5 (PM5) studies for trans-stilbene in its ground, excited (singlet and triplet), and ionic (positive and negative polarons and bipolarons) states. We evaluated the accuracy of the recently developed PM5 method. PM5 and AM1 predict a non-planar ground and singlet states for trans-stilbene, while PM3 predicts planar ones, which is in agreement with the available experimental data. In general the PM3 and PM5 bond lengths are superior to AM1 while AM1 bond angles are superior to PM3 and PM5 when compared with available experimental data. The PM5 underestimates the cis–trans isomerization energy and and it is not a quite reliable method for the calculation of relative IP values. The presumed PM5 superior performance against AM1 and PM3 was not observed for the stilbene structures. [Copyright &y& Elsevier]