Tuberculosis has been an age-old scourge for Filipinos, killing 14,000 in 2015 (according to data from the Department of Health, while the World Health Organization’s estimate is 22,000 in 2016) and putting the Philippines fourth on the WHO list of countries with high TB incidence. Fighting it hasn’t been easy. “Superbugs” or bacteria that have become resistant to existing first-line drugs have emerged due to inappropriate use of medicines, incorrect prescription, or failure to complete the treatment program. Some anti-TB medicines also cause serious side effects.
Filipino scientists have thus been looking for newer and more effective compounds against multi-drug resistant tuberculosis or MDR-TB and extensively drug-resistant tuberculosis or XDR-TB, among other superbugs.
Drug development is a long and expensive process. But in UP, computer-aided drug discovery and development (CADDD) is now helping to reduce the time and cost of drug discovery.
In 2012, a UP research team embarked on a project pioneering the use of computers in discovering new compounds for the treatment of TB. The project was supported until August 2017 by the Office of the Vice President for Academic Affairs (OVPAA) of the UP System under the Emerging Inter-Disciplinary Research (EIDR) program.
Out of around 5 million compounds screened virtually in the computer laboratory set up in UP Manila, the researchers were able to test around a hundred compounds, and then filter down the number of top hits to around ten active compounds, from which three were considered very promising.
The project has officially ended, but according to project leader Junie B. Billones, PhD, a professor in Chemistry at the Department of Physical Sciences and Mathematics of the College of Arts and Sciences (DPSM-CAS), the work goes on. The computational lab for drug discovery, including the software and computers they used, are still there for UP students and researchers to use.
This breakthrough project proved that Filipinos can perform cutting-edge drug discovery and that UP researchers can match what those in universities abroad, with more advanced facilities and equipment, are doing.
Dr. Billones, who was formerly Assistant Director of the Institute of Pharmaceutical Sciences of the National Institutes of Health, says that their group focused on tuberculosis research because TB, a disease caused by Mycobacterium tuberculosis (Mtb), is still a major health issue as the sixth leading cause of death in the Philippines.
“As researchers in a developing country like the Philippines, we should have a contribution on drug discovery to address those areas we feel are quite neglected in terms of drug discovery and development,” Billones adds. This approach is not really new in developed countries because this has been the technique used by large pharmaceutical companies abroad. But as researchers in an academic institution or any research institution in the Philippines, CADDD research is still new in our country.”
The project is unique because it utilizes, for the first time in the Philippines, computer software in the discovery of new compounds. “Typically, new compounds are discovered by chance, by trial and error method,” he explains. “We usually discover new compounds from extracts of plants or organisms, like marine life, sponges. We collect the organisms from the field and then we extract them. We characterize the isolated compounds and then we test the compounds for antibacterial activity, antifungal activity, and effects on other diseases. We use them for assays for different diseases. We are lucky if we find new compounds that can be used for the treatment of a particular disease. It’s really a hit and miss experiment for the longest time; that’s how we discover drugs in the Philippines, really very basic, like finding a needle in the haystack. You really don’t know what is in there and for what purpose.”
This time, however, UP’s researchers tapped the information from database collections of compounds. Says Billones: “We can now pre-select sets of compounds with very promising activity against a certain target. We are reducing the number of compounds to a very manageable number; so our tests in the lab, the bioassay we do in the lab, are for those that give very highly encouraging results, in terms of binding energy, for example, our criterion for activity. We don’t have to spend for a lot of chemicals or specimens for testing millions of compounds since it is impractical and expensive to do so.”
Ten computer units were acquired and installed with software which can perform the functions of “all computational tools in drug discovery, from target modelling to ligand modelling, to modelling interaction between the two, and modification of the top hits, to prediction of ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties that can also be predicted using computational and statistical tools” for the purposes of the project.
Billones says that CADDD is very cost-effective and quite fast compared to typical laboratory experiments. The software’s two-year license fee costs around P1 million, against more expensive equipment in a typical laboratory setup that could cost as high as P50 million.
The UP Manila’s TB Drug Discovery Team includes Maria Constancia O. Carillo, PhD, Voltaire G. Organo, PhD, and other research associates who are also from the DPSM-CAS, UP Manila, and Gisela P. Concepcion, PhD, from the Marine Science Institute, College of Science, UP Diliman. They were also able to publish several articles related to the project in various international scientific journals.
Billones says the project also proves that the Philippines has the expertise to perform this kind of research. “Now, there is an increasing number of paper presentations in conferences, from other research groups in CADDD. There’s an increasing number of scientists in the Philippines going into this kind of work. That’s very encouraging. Drug discovery and development should always be accompanied by modern technologies, CADDD tools in discovering and designing drugs. That’s how pharmaceutical companies abroad are doing it. I’m very thankful to the UP System, especially the OVPAA. I hope other scientists will be able to work with us, to share other structures from compounds, from plants, from bacteria, from any organism in the Philippines. Maybe they can do some testing first, through our facility. They can work with us and we can identify the appropriate bioassay for a particular compound. This speeds up the process of discovery.”