Predicting drug-likeness: why and how?

There exists a huge attrition rate of molecules in clinical trials. It was expected that high-throughput screening and combinatorial chemistry would make the task of producing drugs easier. However, the efforts of the past decade have not been an unvarnished success. As a result, a lot of experimental and computational efforts are currently being directed at determining the basic requirements for a molecule to become a drug. Here we will review the physiological, structural, and other requirements for obtaining a molecule that will be successful in the clinic. Following this we will provide a description, analysis, and commentary on the computational efforts in this direction. We will focus both on the traditional computational chemistry perspective of starting from the structure of the molecule as well as the traditional computational pharmaceutical scientist's perspective of physiologically based simulations. We end with a few comments about the future and some ideas on re-organizing the pharmaceutical enterprise.