The book provides a general introduction to advanced computational techniques applied in various stages of drug discovery. In particular, it focuses on molecular modeling, ligand- and structure-based drug design methods, and data mining in chemical informatics. Application side of this book deals with the development of the first structure-based three-dimensional quantitative structure-activity relationship (3D-QSAR) model of butyrylcholinesterase - a putative drug target for the treatment of Alzheimer's disease. The other part is comprised of detailed work conducted on 5-HT2C agonists. It describes pharmacophore modeling and 3D-QSAR studies. Comparative Molecular Field Analysis coupled with a genetic algorithm (CoMFA-GA) was carried out for aligned ligands. The last part describes the drug target MTB-Thymidine monophosphate kinase (TMPKMtub). The molecular modeling analyses resulted in identification of a cluster of water molecules that mediate key interactions between bound ligands and backbone atoms of the enzyme residues.

Structure Prediction is one of the most important aspects of Structural Bioinformatics, Protein Docking and Drug Designing. The current study is performed on MTHFR enzyme. It plays an important role in folate and homocysteine metabolism by catalyzing the conversion of 5,10-methylenetetrahydrofolate to 5- methyltetrahydrofolate, used for homocysteine remethylation to methionine. MTHFR mutations have been found in a large number of diseases. However, the structure of MTHFR is still unknown, thereby limiting the understanding of structure function relationship to the diseased state. Different Bioinformatics methodologies were used to predict and compare the 3D structure of the wild-type and its mutants. The predicted models were visualized by VMD, RasMol and Pymol. Evaluation of the predicted models was performed using DFIRE, Verify3D, ANOLEA and PROCHECK. Selected Model was compared with its mutants and then simulated. MTHFR mutants were seen to have decreased number of serine phosphorylation sites as compared to wild-type. Phosphorylation seems to be playing a significant role in function of this enzyme.