The explosion of information in structural biology, especially x-ray crystallography of proteins, has begun to have a major impact in drug design, as molecules are developed whose structures are complementary to the structures of their targets. A recent example of this is the HIV protease inhibitors, whose design is based upon the structure of the protease active site. Unfortunately, the high mutation rate of HIV leads to the formation of mutant proteases that are resistant to the inhibitor but are still able to cleave their natural substrates. Multi-drug therapies are used to prolong the efficacy of the treatment. Extensive efforts are currently underway to improve drug delivery, especially in the area of targeting to specific cells.
Some examples follow.
The development of resistance to cytotoxic drugs is the major reason why cancer chemotherapy that starts out successfully subsequently fails. Quite often, a tumor will become resistant not only to the drugs that are given initially, but also to other structurally and functionally unrelated drugs. Such multidrug resistance is caused by the induction in the tumor cell of a transporter called the P-glycoprotein that is encoded by the MDR1 gene. This transporter uses the energy of ATP to pump a variety of different drugs out of the cell, thereby protecting the tumor against chemotherapeutic drugs. When the tumor is exposed for long periods to such drugs, cancer cells that survive are selected because they express high levels of the transporter.