version date: 1 December 2006 Energy carting ener minimum global minimum dihedral angle Graph 1 Local and global minimal energy, respectively, obtained by the minimization process and by molecular dynamic Molecular dynamics can be used to determine the most stable conformation. In this process, the stretching of bonds and angular alterations mimic a procedure of heating the molecule, where the energy barriers between conformations are overcome. An important example is the boat-distorted conformation of cyclohexane as it is minimized by this procedure. Heating the molecule by molecular dynamics generates new conformations including the most stable one, such as the chair. Clonidine(11), the blood anti-hypertension drug, when converted from the 2D-conformation(1la)to the minimized form by molecular mechanics(MM2)(11b)and submitted to molecular dynamics(llc), is a good illustration of the several spatial dispositions. It is important to note the variations in the dihedral angle of the different conformations(11). Structure llc, obtained by molecular dynamics, has the imidazolidine ring closer to a perpendicular orientation toward the 2, 6-dichorophenyl group, which mimics the neurotransmitter, epinephrine, in the interactions with the a receptor(Fig. 7). Another more detailed and systematic procedure may obtain unidentified conformations in the Chem3D program, whereby new ones are gradually generated rotating a central bond and predetermining an angle alteration by the Newman projection. The steric energy in each conformation is determined and represented in energy versus angle graphs, to visualize the most stable ones. This procedure is shown and explored during the laboratory course using acetylcholine(12)as a model. Three techniques are usual in the studies of the conformational properties of (12): X-ray crystallography, nuclear magnetic resonance, and molecular modeling By interacting with different nicotinic and muscarinic receptors in the autonomic nervous system, acetylcholine triggers several biologic effects. Many derivatives in different conformations of the drug have been prepared, but there is still no assurance as to the right receptor-specific conformations. It has been verified, however, that the pharmacophore group should have distinct spatial arrangements in order to interact with nicotinic and muscarinic cholinergic receptors. In this respect, the versatility of the molecule can be explained by the differences in the interatomic distances, 5.9 and 4.4 A between the ester and quaternary ammonium groups, respectively, for the nicotinic and muscarinic receptors interaction. Interatomic distances are directly related to the <www.iupac.org/publications/cd/medicinalchemistry/>9 Energy dihedral angle local minimum global minimum starting energy Graph 1 Local and global minimal energy, respectively, obtained by the minimization process and by molecular dynamics. Molecular dynamics can be used to determine the most stable conformation. In this process, the stretching of bonds and angular alterations mimic a procedure of “heating” the molecule, where the energy barriers between conformations are overcome. An important example is the boat-distorted conformation of cyclohexane as it is minimized by this procedure. Heating the molecule by molecular dynamics generates new conformations including the most stable one, such as the chair. Clonidine (11), the blood anti-hypertension drug, when converted from the 2D-conformation (11a) to the minimized form by molecular mechanics (MM2) (11b) and submitted to molecular dynamics (11c), is a good illustration of the several spatial dispositions. It is important to note the variations in the dihedral angle of the different conformations (11). Structure 11c, obtained by molecular dynamics, has the imidazolidine ring closer to a perpendicular orientation toward the 2,6-dichorophenyl group, which mimics the neurotransmitter, epinephrine, in the interactions with the α2 receptor (Fig. 7).15 Another more detailed and systematic procedure may obtain unidentified conformations in the Chem3D program, whereby new ones are gradually generated rotating a central bond and predetermining an angle alteration by the Newman projection. The steric energy in each conformation is determined and represented in energy versus angle graphs, to visualize the most stable ones.10 This procedure is shown and explored during the laboratory course using acetylcholine (12) as a model. Three techniques are usual in the studies of the conformational properties of (12): X-ray crystallography, nuclear magnetic resonance, and molecular modeling. By interacting with different nicotinic and muscarinic receptors in the autonomic nervous system, acetylcholine triggers several biologic effects. Many derivatives in different conformations of the drug have been prepared, but there is still no assurance as to the right receptor-specific conformations. It has been verified, however, that the pharmacophore group should have distinct spatial arrangements in order to interact with nicotinic and muscarinic cholinergic receptors. In this respect, the versatility of the molecule can be explained by the differences in the interatomic distances, 5.9 and 4.4 Å, between the ester and quaternary ammonium groups, respectively, for the nicotinic and muscarinic receptors interaction.10 Interatomic distances are directly related to the <www.iupac.org/publications/cd/medicinal_chemistry/> version date: 1 December 2006