One goal frequently cited by citizen scientists is to work on problems that benefit human health. Foldit is uniquely positioned to enable this because the game allows players to fold and design proteins, which are often implicated in human disease. In particular, Foldit players can have a huge impact on rare and neglected diseases, which are more common in developing nations than in Western nations and generally receive less attention from pharmaceutical companies. Foldit can help through structure-based drug design (SBDD). The steps involved in SBDD are 1) identification of a target (a protein), 2) crystallization of the target, and 3) design of small-molecule drugs for the target. Through collaboration with the non-profit organization Infectious Disease Research Institute (IDRI), we would like Foldit players to experience this process. We hope that Foldit players will be able to positively impact a specific neglected disease: tuberculosis (TB).
TB is caused by the bacillus Mycobacterium tuberculosis. TB disproportionally impacts impoverished communities and killed 1.5 million people in 2014 alone (2014 is the most recent year that data is available). Additionally, it is estimated that 9.6 million people have fallen ill with TB in 2014, a number that includes 5.4 million men, 3.2 million women, and 1 million children. Figure 1 shows an estimate for incidence rates of TB from the World Health Organization (WHO).
A major issue in treating TB is that the bacterium has evolved to become resistant to current treatments – most notably, antibiotics and even combinations of antibiotics (see WHO for more information on the problem of antibiotic-resistant tuberculosis). The medical community needs a new drug to kill the bacteria; a target and crystal structure for SBDD will greatly accelerate design of new drugs.
Scientists at the non-profit organization Infectious Disease Research Institute (IDRI), and at Eli Lilly, have been working together to identify a suitable target and drug for TB. Their TB Drug Discovery collaboration is embodied in the following video.
These scientists have identified an essential enzyme in M. tuberculosis, LepB, as a target; unfortunately, there is no crystal structure available for the protein to perform SBDD. This protein target is notoriously difficult to work with since it is bound to the cytoplasmic membrane and only small amounts of the protein are available for crystallization trials. More accurate models can be used to guide protein engineering, with the goal of producing more soluble and crystallizable protein. Once crystals have been obtained and X-ray diffraction data obtained, the models will be used for molecular replacement (this is similar to the HIV retroviral puzzle that Foldit players helped solve in 2011). LepB is a difficult target in both experiments and in modeling. The closest homolog to the Protein Data Bank shares ~25% sequence similarity.
This is where citizen scientists can help! We would like to use models created from Foldit players to help solve the crystal structure, once crystals are obtained. These models will have a direct impact on human health, as this target is currently being actively investigated for drug design. Further, this is a prime example of how crowd-sourced citizen scientists, non-profit organizations, and a pharmaceutical company can work in harmony to develop cures for neglected diseases.
The work done here will be published, regardless of the results (e.g., if no crystal structure is obtained due to experimental difficulties, we will still publish Foldit players' models and the players’ names will be on the paper). If crystals are created and a structure is obtained, the players who have models that help with determination of the structure will be on the publication. Rest assured, we will publish what we have so that the whole scientific community can have access to it and help to fight TB.
We are hoping that we can take this puzzle and work through the whole drug design process (through the SBDD process). After models are created, and hopefully a structure is determined, we would like to use the new drug design game elements to design small-molecule drugs against TB as well. You can see in Figure 1 just how much the scientific community needs this.
This puzzle is currently scheduled to appear on Tuesday, 12 July 2016.( Posted by free_radical 83 1426 | Thu, 07/07/2016 - 17:30 | 6 comments )