version date: 1 December 2006 3D structure comparisons and overlay sing the Molecular Modeling Pro [4] program, it is possible to construct 3D interactive drug pictures, optimized by reducing the energy of the molecules in some systematic way until a minimum energy conformer is found. Minimization processes can correct unfavorable bond lengths, bond angles, torsion angles, and nonbonded interactions in a starting structure creating a more stable conformation. Mathematical models that perform geometry optimization are divided into classical, mechanical, and quantum mechanical approaches. In computational chemical simulations, the simplified description is a calculated potential energy surface, which applies classical mechanics equations to molecular nuclei, without considering electrons. A set of equations and parameters is called force field, and most molecular modeling programs can choose among several force fields, such as MM2 and AMBER [5] The energy of any atomic arrangement can be stepwise calculated, by assessing how the energy of the system varies as the position of the atoms change. Molecular Modeling Pro can generate and examine automatically many molecular conformations, and their corresponding inter-conversion energy barriers graphically plotted. At the completion of the conformational analysis, the molecule is placed in its low energy conformation. Both procedures can be interactively performed to optimize the geometry of the molecules that now may be compared structurally by overlaying appropriate atoms or functional groups, previously aligned in the atomic coordinates. Rotation and different representation forms(by charge or lipophilicity ) of the model allow a detailed investigation of the conformational and electronic properties of two structures, which could be the substrate and antimetabolite (inhibitor) Two classes of antineoplastic drugs are chosen to exemplify the structure visualization and superposition processes, which involve compounds that act on target enzymes as thymidylate synthase(Ts, Fig. 1)and dihydrofolate reductase(DHFR, Fig. 2). The purpos <www.iupac.org/publications/cd/medicinalchemistry/> 44 3D structure comparisons and overlays Using the Molecular Modeling Pro [4] program, it is possible to construct 3D interactive drug pictures, optimized by reducing the energy of the molecules in some systematic way until a minimum energy conformer is found. Minimization processes can correct unfavorable bond lengths, bond angles, torsion angles, and nonbonded interactions in a starting structure, creating a more stable conformation. Mathematical models that perform geometry optimization are divided into classical, mechanical, and quantum mechanical approaches. In computational chemical simulations, the simplified description is a calculated potential energy surface, which applies classical mechanics equations to molecular nuclei, without considering electrons. A set of equations and parameters is called force field, and most molecular modeling programs can choose among several force fields, such as MM2 and AMBER [5]. The energy of any atomic arrangement can be stepwise calculated, by assessing how the energy of the system varies as the position of the atoms change. Molecular Modeling Pro can generate and examine automatically many molecular conformations, and their corresponding inter-conversion energy barriers graphically plotted. At the completion of the conformational analysis, the molecule is placed in its low energy conformation. Both procedures can be interactively performed to optimize the geometry of the molecules that now may be compared structurally by overlaying appropriate atoms or functional groups, previously aligned in the atomic coordinates. Rotation and different representation forms (by charge or lipophilicity) of the model allow a detailed investigation of the conformational and electronic properties of two structures, which could be the substrate and antimetabolite (inhibitor). Two classes of antineoplastic drugs are chosen to exemplify the structure visualization and superposition processes, which involve compounds that act on target enzymes as thymidylate synthase (TS, Fig. 1) and dihydrofolate reductase (DHFR, Fig. 2). The purpose <www.iupac.org/publications/cd/medicinal_chemistry/> version date: 1 December 2006