Indian researchers discover a new way to control cholesterol
Researchers have discovered a new frontier in computer-aided drug discovery that could help develop drugs that can block harmful protein-protein interactions that lead to conditions such as increased low-density lipoprotein (LDL) or cholesterol levels.
Proteins are vital to our health, performing a wide range of functions. However, incorrect protein interactions can lead to diseases. Traditionally, scientists have tried to develop small molecule drugs that act as competitive inhibitors for protein-protein interaction (PPI) sites. However, this has proven difficult due to the large and smooth nature of protein interaction regions.
An alternative approach uses larger peptides or antibodies to block PPIs, although these can be expensive and difficult to administer. So the pharmaceutical industry looks for smaller molecules that are easier to take, usually in pill form. One promising new method involves allosteric inhibitors – drugs that bind to different parts of a protein, changing its behaviour and preventing harmful interactions.
The challenge is to identify these special target points on the protein. The researchers have proposed a new computational protocol to predict and identify alternative binding pockets and hotspots on the protein surface allosterically coupled to the functional site using advanced computer simulation approaches.
As a test case, they examined PCSK9, a protein that regulates cholesterol levels by interacting with the low-density lipoprotein receptor (LDLR). An increase in the PCSK9-LDLR interaction can raise LDL levels, which contributes to heart disease. Current treatments that target PCSK9 are expensive and not suitable for everyone. Finding an orally administered small-molecule drug that blocks the PCSK9-LDLR interaction could be transformative.
Dr Suman Chakraborty's team has made significant progress in identifying targetable parts of the PCSK9 protein. They used thermodynamics to argue that the bidirectional nature of allostery could identify allosteric pockets. By comparing conformational groups of bound and unbound protein states, they propose targeting unique conformations in the unbound state for drug discovery. This collaborative approach between academia and industry aims not only to reduce cholesterol but also to establish a new paradigm in drug design, targeting proteins more effectively for disease prevention.
