QSARs and MDS combined to estimate potency, absorption and distribution properties of drug candidates

4D-QSAR analysis is a molecular modeling method that incorporates ligand conformational flexibility, multiple alignment exploration and exhaustive evaluation of ligand embedded pharmacophore groupings in the QSAR model building process. Two series of analogs were studied by employing the 4D-QSAR method. The first series was a set of propofol analogs with general anesthetic effects. Through the construction of 4D-QSAR models for three screens of biological activity of the propofol analogs it was found that GABAA contains the receptor the likely site of propofol's anesthetic action. Distinct 3D pharmacophores, which are indicative of specific ligand-receptor binding, were also identified.; The second series of compounds studied were 38 flavone analogs that possess selective and relatively mild affinities, for the benzodiazepine binding site on the GABAA receptor. The -logKi values of the flavones were found to be highly dependent on both the size and the electrostatic character of the substituents at the R3' and R6 positions of the flavonoid scaffold. The results from these two studies can be used to design more potent ligands for the GABAA receptor.; In addition to potency, a good ADMET profile is also highly desirable for a compound to qualify as a drug. (ADMET stands for absorption, distribution, metabolism, elimination and toxicity.) The ADMET properties of a set of antimycobacterial drugs were studied using conformational analysis and molecular dynamics simulation, and emphasis was put on modeling the permeability of this series of drugs across the Mycobacterium tuberculosis cell wall. Mycolic acid molecules, that are the main component of the M. tuberculosis cell wall, were found to be tightly packed and to exist in a relatively highly ordered state. The molecular shape of the solute appears to be an important factor for permeation through the M. tuberculosis cell wall. Predominant lateral diffusion within, as opposed to transverse diffusion across, the membrane/cell wall system was observed for some drugs. The extent of lateral diffusion relative to transverse diffusion of a solute within a biological cell membrane may be an important consideration with respect to ADMET properties of drug candidates.