Raina Pang
Jun 4, 2012

Speeding up drug development

Using their new rapid technique, the Salk Institute team generated the structure of a hIMP known as TMEM14A, shown here.As patents on major, money-making pharmaceuticals such as Lipitor, Plavix and Zyprexa run out and begin to face generic competition, drug companies have been struggling to recoup the loss of revenue through drug development. Traditionally, this process has been expensive and provides inefficient output. Outsourcing early drug development to academia and specialist companies has been proposed as a way to improve this process. The collaborative nature of these interactions would allow large pharmaceutical companies to focus on large clinical trials and marketing. Furthermore, these types of collaborations could provide a more targeted approach to choosing drugs to move into the later stages of testing.

Some of this academic research has focused on 3D modeling to improve the ability to target certain proteins. For example, combining 3D modeling and augmented reality provides insight into how potential drug candidates and infectious agents interact, and the energy requirements for them to bind. Effective targeting of infectious agents depends on this interaction. Thus, those compounds that show good interactions should be the most effective.

While 3D modeling provides a basis for understanding the interaction between a therapeutic agent and a target, the efficiency of this approach depends on the ability to accurately model the target protein, a historically slow process.

Human integral membrane proteins (hIMPs) are a key set of these target proteins. In fact, they serve as targets for half of current pharmaceuticals, including treatments for Alzheimer’s disease, heart disease and cancer. Because of the importance of these proteins in diseases, understanding their 3D shape could greatly reduce the amount of drug scanning required to find suitable effective pharmaceuticals. Unfortunately, traditional methods for identifying the structure of these proteins have been extremely slow, resulting in the identification of approximately one protein a year. This slow process means that of the estimated 8,000 human integral membrane proteins only about 30 structures have been identified. Innovation from researchers at the SALK institute, however, appears to greatly speed up the 3D modeling of human integral membrane proteins.

Through looking at structures in a free cell expression system, in which the internal cell environment that allows for hIMPs to grow is recreated outside of a cell,  researchers were able to view the synthesis of proteins outside of the cell environment. With this approach, researchers controlled the incorporation of specific, labeled amino acids. The magnetic properties of the atom could be determined through nuclear magnetic resonance spectroscopy applied to proteins made from the introduction of the carefully labeled and controlled amino acids. This allowed for an understanding of the physical and chemical properties and provided essential clues about the protein's structure. This process seems to greatly speed up the identification of new structures with the completion of six structures in eight months.

Drug development is going through a growing phase. In contrast to the brute force of extensive scanning, understanding of biochemical interactions could improve productivity by reducing the scanning process. In particular, 3D modeling has provided important clues about energy requirements and the specifics of therapeutic and target binding. Innovative approaches to this modeling, like this one applied to hIMPs, could speed up this process, greatly improving the speed of drug development.