Research Projects

This study focuses on carbonic anhydrases (CAs), a group of zinc-containing metalloenzymes that catalyse the reversible hydration of CO₂ into bicarbonates and protons, and plays a critical role in physiological processes like regulation of blood pH, respiration system, and tumorigenesis etc. The research aims to investigate the structural differences and inhibition mechanisms of human carbonic anhydrase (hCAs) isoforms in complex with non-classical carbonic anhydrase inhibitors (CAIs), to develop isoform-specific inhibitors for targeted drug delivery, minimising the undersirable side effects associated with classical (sulfonamide based compounds) CAIs. Among different classes of CAs, specifically, α-class of CAs, are pivotal in human pathology, with isoforms associated in diseases such as glaucoma, cancer, epilepsy, neurodegenerative disorders and altitude sickness. CAs are generally inhibited by classical CA inhibitors, like sulfonamides or sulfonamides-based compounds, often resulting in off-target drug binding effects and other side effects such as nausea, drowsiness, and organs damage. While sulfonamide-based compounds still remain in medical treatments and clinical trials, the research is shifting from classical to non-classical CAIs, utilising alternative zinc-binding groups for isoform-specific inhibition. Identification of various CA isoforms as therapeutic targets for multiple diseases has sparked the interest in designing isoform-specific inhibitors to develop more effective treatment and to reduce the side effects associated with sulfonamide CAIs. Hence, in this context, non-classical CAIs, such as phenols, fullerenes, polyamines, and carboxylic acids, offer an alternative by targeting specific isoforms more selectively, and potentially reducing side effects. Therefore, this research project will employs molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) methods to explore the binding mechanisms of non-classical CAIs and their interactions with various hCA isoforms. By investigating the structural-activity relationship of the enzyme active site clefts and binding energetics of these inhibitors, the research will provide insights into how non-classical inhibitors can be optimised for more selective and effective therapeutic applications. The research work will also investigate the molecular basis of resistance to CAIs, analysing enzyme-ligand interactions to identify how changes in binding affinities and the hydrogen-bonding networks might contribute to reduced inhibitor effectiveness. Our findings are expected to deepen the understanding of properties and mechanisms of non-classical CAIs, providing new insights into how these inhibitors can be modulated for therapeutic purposes. In short, the work outcomes are expected to provide computational insights aiding in the advancement of design of isoform-selective inhibitors by leveraging MD and QM/MM methods.