New computational approach promises cost-effective cholesterol control solution

New Delhi: In a significant breakthrough for drug discovery, researchers have developed a computational protocol that promises a cheaper and more effective approach to managing cholesterol levels. This method targets protein-protein interactions (PPIs), which can lead to conditions like elevated low-density lipoprotein (LDL) or cholesterol levels, often contributing to heart disease.

Proteins are essential for maintaining various bodily functions, but incorrect interactions between them can result in numerous diseases. Traditionally, scientists have focused on developing small molecules to act as competitive inhibitors, blocking harmful PPIs without affecting beneficial interactions. However, the challenge lies in finding drugs that can effectively target the often large and smooth interaction surfaces of proteins, which lack obvious binding sites.

Larger peptides or antibodies have been used to inhibit PPIs, but these options are costly, difficult to store, and require injection. Therefore, the pharmaceutical industry is keen on finding small molecules that can be administered orally.

A promising alternative is the use of allosteric inhibitors, which bind to different protein regions, influencing their behavior and preventing harmful interactions. Identifying these allosteric sites is challenging, as they are often transient or hidden.

This challenge has been addressed by Dr. Suman Chakrabarty and his team at the S. N. Bose National Centre for Basic Sciences, Kolkata, in collaboration with Sarfez Pharmaceuticals. Their research, published in the Journal of Chemical Information and Modelling, introduces a computational protocol to predict and identify alternative binding pockets on proteins that are allosterically linked to functional sites (PPI interfaces) using advanced simulations.

The team focused on PCSK9, a protein that regulates cholesterol levels by interacting with low-density lipoprotein receptor (LDLR). Increased PCSK9-LDLR interaction elevates LDL levels, a key factor in heart disease. Current PCSK9-targeting treatments are expensive and not suitable for all patients, highlighting the need for an oral small-molecule drug to block this interaction effectively.

Dr. Chakrabarty’s team has identified potential target areas on the PCSK9 protein for these small-molecule drugs. By leveraging basic thermodynamics, they demonstrated that the bidirectional nature of allostery can reveal allosteric pockets. Their approach involves comparing the conformational ensembles of bound and unbound protein states, targeting unique conformations and pockets in the unbound state for drug discovery.

This collaboration between an academic research laboratory and a pharmaceutical company is focused not only on lowering cholesterol but also on developing new strategies to prevent diseases by targeting proteins more intelligently.