Research Interests

Cyclophilin A-Cyclosporin A Crystal Complex (PDB: 1CWA)

Macrocyclic Drug Discovery

Drugging the undruggables: Contemporary drug discovery campaigns have aimed to expand the boundary of druggable target proteins which are at present known to represent merely ~15% of the entire human proteome. Among various drug modalities to achieve this goal, macrocycles have gained much attention from medicinal chemists due to their constrained three-dimensional shapes and large surface areas, which enable selective binding to conventionally undruggable targets such as protein-protein interactions (PPIs). Our research interests mostly focus on solving challenging issues in drug discovery using synthetic macrocycles, especially cyclic peptides. These issues include not only enhancing the potency and selectivity of macrocycles, but also improving poor membrane permeability arising from their large size.

Modification of Macrocyclic Conformation

Preorganization of macrocycles resulting from cyclization leads to the stabilization of specific conformations, thereby facilitating target engagement by minimizing entropic loss. Conformation is the ultimate determinant of ligand binding events, thus, developing methods for conformational control of macrocycles in a predictable manner is of great importance. Due to their cyclic nature, relatively minor structural modifications to a macrocycle can alter the overall conformation because local conformational changes propagate along the ring to affect distal structural features. Considering this unique feature, our strategy for developing novel conformation-controlling/restricting reactions is categorized into three approaches: (a) efficient macrocyclization, (b) late-stage addition of an exocyclic element, and (c) conformational switching via endocyclic editing. This research would streamline the establishment of a conformationally diverse macrocycle library.

Conventional Drug Discovery

Small molecules (MW <500 Da) have formed the foundation of modern drug discovery for over a century, owing to their predictable physicochemical properties, excellent oral bioavailability, and ease of synthesis. As followers of this powerful tradition, we are also focusing on a wide range of topics in small molecule-based drug discovery programs including the total synthesis of natural products, the development of novel synthetic methods, and the optimization of bioactive molecules. Currently, we are exploring DAMP modulators, EndMT blockers, and anti-MRSA agents.

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