Drug discovery is an arduous, high-cost endeavor. It is a symphony of multiple disciplines, such as genomics, bioinformatics, and medicinal chemistry. Computational methods, over the years, have become an integrated part of drug discovery. They are involved in a few different spots of drug development pipeline and utilized to help in cutting cost and time. In this talk, I will highlight some of my group’s efforts on development and applications of computational methods for drug discovery. Some of the results of our work have made their way into commercial software used in computational drug discovery. The talk will be in two parts. I will first present applications of quantum chemical calculations to docking. Second, I will introduce the water-based pharmacophore model, which incorporates molecular dynamics simulations with explicit water molecules into ligand screening and drug design. The emphasis will be on introduction of computer simulation technologies which are revolutionizing drug discovery processes.