IIT Madras researchers to develop more effective drugs against HIV-AIDS

NEW DELHI: Researchers at the Indian Institute of Technology (IIT), Madras are working on a new idea using molecular dynamics simulations that can help develop more effective drugs for treating HIV. The research team has found that introducing electrostatic interaction sites on potential drug molecules can enhance the efficacy of antiviral drugs against the HIV virus.

The research has been published in the prestigious peer-review journal of the American Chemical Society – Biochemistry. "AIDS is one of the most devastating diseases and is a major cause of death among youths in many parts of the world. Since its outbreak nearly four decades ago, tremendous efforts have been directed towards the development of antiretroviral therapies that target different stages in the life cycle of the virus that causes this deadly disease," said Sanjib Senapati, Department of Biotechnology, IIT Madras.

"The pressing need for better drugs to combat drug-resistant HIV strains led our researchers to delve into the molecular structure of the protease to identify weak sites that can offer a handle for better inhibitor development," he added. According to the team, one of the routes that drug developers work on is to attack HIV-1 protease (HIVPR), an essential enzyme that is used by the AIDS virus for growth and maturation. Drug designers have aimed at developing efficient inhibitors of the enzyme – inhibitors are molecules that bind with the enzyme, thereby making it unavailable to the virus for growth and maturation. "Current inhibitors that target HIVPR make use of the weak forces of attraction, called 'Van der Waals' forces', to attach themselves to the protease molecule. Given that these forces are weak, the efficacy of the drug is variable and the virus will soon become resistant to them," Senapati said.

Vital data for design

"Recent useful data obtained using analytical techniques such as neutron diffraction and NMR, on the molecular structure of the target HVPR enzyme, have encouraged us to revisit the patterns of HVPR-inhibitor binding. By using the state-of-art computational techniques, the team has uncovered vital data that can be used for design of more efficacious drugs," he said. The Molecular Dynamics (MD) simulation studies conducted by IIT Madras researchers showed the presence of a strong and asymmetrical electric charge in the active site of the HIVPR.

"If a drug molecule can be designed with a complementary charge, so that it can bind tightly with this active site through electrostatic attraction, it can permanently deactivate or inhibit the enzyme. "Current drugs lack this electrostatic complementarity. This must be investigated because it is well known that electrostatic forces between molecules are much stronger than Van der Waals' forces," Senapati said.

"We propose that drug design strategies should embrace both electrostatic and Van der Waals' forces interactions to complement the HIVPR active site architecture. "Further, the team believes that such compounds will be effective against both wild type and resistant HIV variants. This is a paradigm-shifting idea and will offer a whole new approach for the development of drugs for HIV-AIDS," he said.

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