version date: 1 December 2006 with high precision. a big drawback in PM3 concerns the charges as a consequence of quite fiery parameter values Based on our experience, both models perform in the same way on data such as heats of formation, while problems were encountered with the PM3 model in minimum energy con- formations. In terms of the actual NDDO model, PM3 allows most of the parameter values to float resulting in substantially more parameters whether AMl has a different"view"in the application of the Gaussian functions considered as patches and introduced to adjust the core-electron/core electron repulsion function. The addition of Gaussian functions to some of the core repulsion func- tions(CRFs) for certain elements is a substantial difference between the two models. These func- tions have a position, a width, and an intensity, all of which can be taken as parameters. They were initially intended to adjust the SHAPE of the CRF so that it woulg. specific types of systems that re closely correspond to"re could not be handled in general parameterization without disrupting other chemically important items. To avoid failures common in all the models PM3 includes de novo two gaussian functions for each element, which strongly belittles thechemical reality Dewar, M.J.S., Healy, E F, Holder, A.J., Yuan, Y-C. "Comments on a comparison of AMI with the recently developed PM3 method",J. Comp. Chem. 11, 541-542(1990) Holder, A.J., Dennington, R.D., Jie, C " Addendum to SAMI results previously published 7 etrahedron50,627-638(1994) Stewart, J.J. P "MOPAC: A Semiempirical Molecular Orbital Program", J. Computer-Aided Mol.Des.4,1-105(1990) Gundertofte, K, Palm, J, Pettersson, I, Stamvik, A "A comparison of conformational energi calculated by molecular mechanics(MM2(85),Sybyl 5.1, Sybyl 5.21, and ChemXr-and semiempirical(AMI and PM3 )methods'",J Comp. Chem. 12, 200-208(1991) Among SPARTAN's properties module's functions, there is the calculation of log P Two log P models are available: Villar and Ghose-Crippen. The first is a model that only works on semi-empirical wavefunctions with no d-orbitals. The Villar method examines the over- lap matrix, searching for the type and number of lone pairs as well as the surface area of each atom It is parameterized for H, C,N, O, F, S, and CI Ghose-Crippen is the spartan default method of calculating log P. This method depend only on the connectivity of the molecule, and it is independent of the wavefunction (i.e, one will et the same results for semi-empirical, HF, and DFT methods but this depends on how the mole cule is drawn/connected). The Ghose-Crippen model is parameterized for 110 atom types, includ ing common bonds of H, C, N,O, S, and the halogens. Avoiding correction factors was obtained evaluating the hydrophobicity on an individual atom basis, accounting for the undeniable in- tramolecular interactions by employ ing a large number of atom types The Villar method is an alternative atom-based method for the computation of a conformation- ally dependent hydrophobic quantity(p). The parameters used in this method are the molecular sur- faces and atomic charges, both of which have some dependency on the conformation adopted by he system, as well as a set of adjustable parameters that only depend on the atomic number. These adjustable parameters were determined by linear regression using experimental values of the octa- nol/water partition coefficient The quantity p differs from the actual octanol/water partition coefficient, which is a macro- scopic property. Only if one conformer is accessible as in rigid compounds, are these two quantities equal. Even though the calculation of partition coefficients can be made using the hydrophobic in- dices described here, their computation would require a cumbersome statistical averaging for flexi- ble analogs. In general, this procedure is not recommended for the computation of the property when the methods proposed in the past can provide similar or better accuracies without the com- putational effort. One possible exception could be some types of isomery(see above, Isosterism, Bioisosterism, and Bioanalogy and the exercise below) which current methods for calculating <www.iupac.org/publications/cd/medicinal_chemistry/>7 with high precision. A big drawback in PM3 concerns the charges as a consequence of quite fuzzy parameter values. Based on our experience, both models perform in the same way on data such as heats of formation, while problems were encountered with the PM3 model in minimum energy con￾formations. In terms of the actual NDDO model, PM3 allows most of the parameter values to float, resulting in substantially more parameters whether AM1 has a different “view” in the application of the Gaussian functions considered as patches and introduced to adjust the core-electron/core￾electron repulsion function. The addition of Gaussian functions to some of the core repulsion func￾tions (CRFs) for certain elements is a substantial difference between the two models. These func￾tions have a position, a width, and an intensity, all of which can be taken as parameters. They were initially intended to adjust the SHAPE of the CRF so that it would more closely correspond to “re￾ality”, whatever that is. In essence, they were used as patches for specific types of systems that could not be handled in general parameterization without disrupting other chemically important items. To avoid failures common in all the models, PM3 includes de novo two Gaussian functions for each element, which strongly belittles the “chemical” reality. • Dewar, M.J.S., Healy, E.F., Holder, A.J., Yuan, Y-C. “Comments on a comparison of AM1 with the recently developed PM3 method”, J. Comp. Chem. 11, 541–542 (1990). • Holder, A.J., Dennington, R.D., Jie, C. “Addendum to SAM1 results previously published”, Tetrahedron 50, 627–638 (1994). • Stewart, J.J.P. “MOPAC: A Semiempirical Molecular Orbital Program”, J. Computer-Aided Mol. Des. 4, 1–105 (1990). • Gundertofte, K., Palm, J., Pettersson, I., Stamvik, A. “A comparison of conformational energies calculated by molecular mechanics (MM2 (85), Sybyl 5.1, Sybyl 5.21, and ChemX) and semiempirical (AM1 and PM3) methods”, J. Comp. Chem. 12, 200–208 (1991). Among SPARTAN’s properties module’s functions, there is the calculation of log P. Two log P models are available: Villar and Ghose–Crippen. The first is a model that only works on semi-empirical wavefunctions with no d-orbitals. The Villar method examines the over￾lap matrix, searching for the type and number of lone pairs as well as the surface area of each atom. It is parameterized for H, C, N, O, F, S, and Cl. Ghose–Crippen is the SPARTAN default method of calculating log P. This method depends only on the connectivity of the molecule, and it is independent of the wavefunction (i.e., one will get the same results for semi-empirical, HF, and DFT methods but this depends on how the mole￾cule is drawn/connected). The Ghose–Crippen model is parameterized for 110 atom types, includ￾ing common bonds of H, C, N, O, S, and the halogens. Avoiding correction factors was obtained evaluating the hydrophobicity on an individual atom basis, accounting for the undeniable in￾tramolecular interactions by employing a large number of atom types. The Villar method is an alternative atom-based method for the computation of a conformation￾ally dependent hydrophobic quantity (p). The parameters used in this method are the molecular sur￾faces and atomic charges, both of which have some dependency on the conformation adopted by the system, as well as a set of adjustable parameters that only depend on the atomic number. These adjustable parameters were determined by linear regression using experimental values of the octa￾nol/water partition coefficient. The quantity p differs from the actual octanol/water partition coefficient, which is a macro￾scopic property. Only if one conformer is accessible as in rigid compounds, are these two quantities equal. Even though the calculation of partition coefficients can be made using the hydrophobic in￾dices described here, their computation would require a cumbersome statistical averaging for flexi￾ble analogs. In general, this procedure is not recommended for the computation of the property when the methods proposed in the past can provide similar or better accuracies without the com￾putational effort. One possible exception could be some types of isomery (see above, Isosterism, Bioisosterism, and Bioanalogy and the exercise below) which current methods for calculating <www.iupac.org/publications/cd/medicinal_chemistry/> version date: 1 December 2006