New Delhi: Researchers at Kolkata’s S. N. Bose National Centre for Basic Sciences conducted research into a novel approach to treating diseases, including high cholesterol or low-density lipoprotein, or LDL.
Proteins are essential to our health because they carry out so many different tasks. However, illnesses can result from improper interactions between proteins. Historically, researchers have worked to create small-molecule medications that competitively block protein-protein interaction (PPI) sites. However, as protein interaction regions are smooth and broad, this has proven challenging.
Large peptides or antibodies are another strategy that inhibits PPIs, although they can be expensive and challenging to deploy.
Pharmaceutical industries thus seek small molecules that are easier to take, typically in pill form.
A promising new method involves allosteric inhibitors—drugs that bind to different protein parts, changing their behaviour and preventing harmful interactions.
Finding these unique target locations on proteins is a problem. Using sophisticated computer simulation techniques, the researchers suggest a novel computational strategy to predict and locate alternative binding pockets and hotspots on a protein surface that are allosterically related to the functional site.
As a test case, they examined PCSK9, a protein that controls cholesterol levels by interacting with low-density lipoprotein receptors (LDLR). Increased PCSK9-LDLR interaction can elevate LDL levels, contributing to heart disease. Current treatments targeting PCSK9 are expensive and not suitable for everyone. However, the potential discovery of an orally administered small-molecule drug that blocks the PCSK9-LDLR interaction could be truly transformative in the field of disease prevention.
Dr Suman Chakrabarty’s team, in a collaborative effort with the pharmaceutical industry, has made significant progress in identifying targetable parts of the PCSK9 protein. They used thermodynamics to argue that the bidirectional nature of allostery can identify allosteric pockets. By comparing the conformational ensembles of bound and unbound protein states, they propose targeting unique conformations in the unbound state for drug discovery. This collaborative approach aims not only to lower cholesterol but also to create a new paradigm in drug design, targeting proteins more effectively to prevent diseases.
–IANS
