version date: 1 December 2006 of conformational analysis and energy minimization. The method of choice for the minimization of energy is dependent both on the size of the molecule and the availability of stored data and parameters, as well as computational resources. Computer-generated molecular models are based on mathematical equations that estimate positions and properties of electrons and nuclei; furthermore, the added calculations experimentally explore the structure, producing a molecule under new perspectives A Molecular mechanics Energy is calculated by comparing angles and distances bonds in a molecule, using values that are listed by the MM2 program. Molecular mechanic equations only consider atomic nuclei and do not include electrons in the calculations. The interactions due to stretching of bonds, angular torsional and spatial deformation are determined by the program, which also calculates the energy of the starting molecule comparing it with a standard, methane( KJ/mol). The program of molecular mechanics resulting in new conformations and the corresponding energy calculation modifies angles and lengths of the original atomic bonds The program also recognizes changes leading to more stable structures with lower steric energy, but the calculations are interrupted if the variation in energy in relation to the original molecule is not considerable. Although molecular mechanics predict energy associated to a particular conformation the quantities expressed are not absolute ones, but only differences between two or more conformations. 0 B. Quantum mechanics In this process, properties of the molecule are calculated by equations of quantum physics, involving interactions between electron and nuclei. Electron movements are more rapid and, since they rotate independently of the nucleus, it is possible to describe electronic energy separately from the nuclear one. Some approximations based on empirical data ar re made in calculations by this process, which are not exact and may be executed by two methods, ab initio and semi-empiric. The first one, is applied only to small molecules, and although more precise and not needing stored data, requires ample computer memory capacity and time. On the other hand, the semi-empiric method is faster and can be used to minimize energy and optimize molecules with 10 to 120 atoms, although less accurate Energy is calculated by the Schrodinger equation from stored parameters; MOPAC is the most frequently used semi-empiric method, subdivided into the following: AMI MINDO/3, MNDO, MNDO-d, and PM3. Figure 6 shows chlorpromazine(9)and indomethacin(10). In these drugs, the biologic effect is highly dependent on certain conformations for the receptor interactions. There is an obvious difference in spatial arrangements between non-optimized forms(9b and 10b)and the corresponding(9c and 10c), energetically optimized by the program MOPAC (AMI). The tricyclic system of the antipsychotic chlorpromazine(9a)in the planar form does not seem to react with the dopaminergic receptor, but it does in an angle of approximately 25 in the ring junction that coincides with structure(9c). Indomethacin(10a), however, shows relevant features for anti-inflammatory activity, such as the nonplanar or perpendicular orientation of the N-p chlorobenzylic group in relation to the indolic system. Structure 10c, closer to the bioactive conformation can be obtained by minimizing structure 10b, relatively planar. A more detailed visualization of 3D minimized molecules can be obtained by movements around axis X, Y, and Z, with the help of the"mouse <www.iupac.org/publications/cd/medicinalchemistry/>7 of conformational analysis and energy minimization.10 The method of choice for the minimization of energy is dependent both on the size of the molecule and the availability of stored data and parameters, as well as computational resources. Computer-generated molecular models are based on mathematical equations that estimate positions and properties of electrons and nuclei; furthermore, the added calculations experimentally explore the structure, producing a molecule under new perspectives. A. Molecular mechanics Energy is calculated by comparing angles and distances bonds in a molecule, using values that are listed by the MM2 program. Molecular mechanic equations only consider atomic nuclei and do not include electrons in the calculations. The interactions due to stretching of bonds, angular torsional and spatial deformation are determined by the program, which also calculates the energy of the starting molecule comparing it with a standard, methane (1 KJ/mol). The program of molecular mechanics resulting in new conformations and the corresponding energy calculation modifies angles and lengths of the original atomic bonds. The program also recognizes changes leading to more stable structures with lower steric energy, but the calculations are interrupted if the variation in energy in relation to the original molecule is not considerable. Although molecular mechanics predict energy associated to a particular conformation the quantities expressed are not absolute ones, but only differences between two or more conformations.10 B. Quantum mechanics In this process, properties of the molecule are calculated by equations of quantum physics, involving interactions between electron and nuclei. Electron movements are more rapid and, since they rotate independently of the nucleus, it is possible to describe electronic energy separately from the nuclear one. Some approximations based on empirical data are made in calculations by this process, which are not exact and may be executed by two methods, ab initio and semi-empiric. The first one, is applied only to small molecules, and although more precise and not needing stored data, requires ample computer memory capacity and time. On the other hand, the semi-empiric method is faster and can be used to minimize energy and optimize molecules with 10 to 120 atoms, although less accurate. Energy is calculated by the Schrödinger equation from stored parameters; MOPAC is the most frequently used semi-empiric method, subdivided into the following: AM1, MINDO/3, MNDO, MNDO-d, and PM3.10 Figure 6 shows chlorpromazine (9) and indomethacin (10). In these drugs, the biologic effect is highly dependent on certain conformations for the receptor interactions. There is an obvious difference in spatial arrangements between non-optimized forms (9b and 10b) and the corresponding (9c and 10c), energetically optimized by the program MOPAC (AM1). The tricyclic system of the antipsychotic chlorpromazine (9a) in the planar form does not seem to react with the dopaminergic receptor, but it does in an angle of approximately 25° in the ring junction, that coincides with structure (9c). Indomethacin (10a), however, shows relevant features for anti-inflammatory activity, such as the nonplanar or perpendicular orientation of the N-p￾chlorobenzylic group in relation to the indolic system.13 Structure 10c, closer to the bioactive conformation can be obtained by minimizing structure 10b, relatively planar. A more detailed visualization of 3D minimized molecules can be obtained by movements around axis X, Y, and Z, with the help of the “mouse”. <www.iupac.org/publications/cd/medicinal_chemistry/> version date: 1 December 2006