Drugs for neglected illnesses

Researchers seek to identify target biological receptors and uncover their structures to discover candidate molecules for new drugs.

By Elton Alisson

Agência FAPESP – In the last few decades, the United States Food and Drug Administration (FDA) has authorized roughly 1,400 new molecules for human trials to treat illnesses. Of this total, only 16 were utilized to treat neglected tropical diseases (NTD), the classification for certain infectious diseases that develop in hot, humid climates and affect more than 1 billion impoverished people in Africa, Southeast Asia, Latin America and the Caribbean, according to World Health Organization data (WHO).
 
In an attempt to discover candidate molecules for new drugs to treat these diseases that have been largely ignored by pharmaceutical industries and have been treated instead with very old medicines – which have the dual problem of low efficacy and high toxicity – Brazilian researchers are conducting studies to identify target biological receptors and uncover their structures.

The results of some studies conducted in the area were presented at the fifth event in the Cycle of Conferences for the International Year of Chemistry 2011. The event was entitled “Neglected diseases and the challenges of developing new medicine” and was held on September 14 at FAPESP’s auditorium.

According to Glaucius Oliva, president of the National Council of Scientific and Technological Development (CNPq) and professor at the Physics Institute of Universidade de São Paulo’s São Carlos campus, unlike the 1960s when in order to develop new medicine a scientist first obtained the molecules to test them in an animal model, the modern day process is the opposite.

“Today, one seeks to identify the target biological receptor first and then its structure in order to attempt to block it, and lastly, to synthesize and find a molecule in nature,” says Oliva.

A researcher at the Structural Molecular Biotechnological Center (CBME) – a FAPESP Research, Innovation and Diffusion Center (CEPID) which also houses the National Institute of Science and Technology in Structural Biotechnology and Medicinal Chemistry for Infectious Diseases (INBEQMeDI) – Oliva and his team described the structure of an essential enzyme for Trypanosoma cruzi, the causing agent of Chagas Disease, which could be the target receptor for new medicine to treat the disease.

Utilizing the X-ray diffraction technique, the researchers revealed the crystallographic structure of glyceraldehyde – 3 phosphate  dehydrogenase (GAPDH), an enzyme that plays a fundamental role in the glucose metabolism of the parasite.

The discovery created the possibility for scientists to plan new medicine to treat the disease based on the structure of this biological target receptor. “Through physical techniques to study molecular structure like X rays, synchrotron radiation and nuclear magnetic resonance, among others, physicists can contribute to the development of new drugs,” says Oliva.

According to Oliva, the two main criteria utilized for finding a molecule that attaches to a new biological target receptor is the complementarity of its shape and its chemical properties so that the main active ingredient will have the desired pharmacological action in the human organism.

In order to facilitate studies of the properties of existing main active ingredients in new biological target receptors, the researchers at CBME’s Medicinal and Computational Chemistry Laboratory have developed a database for the study of pharmacokinetic properties and in silico development for prediction of absorption, distribution, metabolism and excretion.

The Database for Pharmacokinetic Properties (PK/DB) can be accessed from the laboratory’s site and boasts data on more than 1,400 compounds, detailing their specific respective properties.

“The database presents more than 4,000 compound measurements, including intestinal absorption and bioavailability in humans, and is a very interesting tool in the search for molecules. One need only input the name of molecule to see its molecular shape and pharmacological action,” says Adriano Andricopulo, professor at the Physics Institute at USP- São Carlos and coordinator of the laboratory.

According to him, the database recently gained a tool that allows users to search by molecular fragment for planning of new molecules. The search tool allows users to study the role of each molecule in different drugs launched on the market.

 The researchers are developing a new tool to conduct virtual screening of molecules with the greatest potential for experimental testing in laboratories in a biological target receptor. “With the new tool, one can select molecules that are already physically available and conduct biological screening tests in labs with a well defined target,” says Andricopulo.

The Database for Pharmacokinetic Properties (PK/DB) can be accessed in: http://miro.ifsc.usp.br/pkdb.

Sponsored by the Brazilian Chemistry Society (SBQ) in partnership with the FAPESP’s Pequisa magazine, the event is par of the official celebrations for the International Year of Chemistry, promoted by the United Nations Education, Science and Culture Organization (Unesco) and the International Union of Pure and Applied Chemistry (Iupac).

The cycle is coordinated by Vanderlan da Silva Bolzani, professor of the Araraquara Chemistry Institute at Universidade Estadual Paulista (Unesp) and SBQ’s member to the national activities committee for the International Year of Chemistry 2011, and Mariluce Moura, news director at the magazine.

More information: www.fapesp.br/eventos/aiq