Research
Our laboratory focuses on drug discovery and chemical biology, with the goal of developing first-in-class small-molecule chemical probes and drug candidates that enable target validation and translational therapeutic development. We integrate medicinal chemistry, structural biology, virology, computational modeling, and pharmacology to understand how small molecules interact with biological targets and to design compounds with improved potency, selectivity, and resistance profiles.
Our research spans viral and host targets involved in infectious diseases as well as cancer-related pathways, and combines structure-based drug design, artificial intelligence–assisted modeling, biochemical and cellular assays, and in vivo studies to advance compounds from early discovery to preclinical evaluation.
Our research program is organized around five major themes.
1. AI-Driven Drug Design and Computational Modeling
Artificial intelligence and computational modeling are increasingly transforming early-stage drug discovery. We integrate AI-based molecular design and physics-based modeling to accelerate hit identification and lead optimization.
Our work includes de novo library generation using generative AI models, AI-based virtual screening and affinity prediction, and the application of machine learning models to predict antiviral activity, cytotoxicity, and selectivity. These approaches are complemented by molecular docking and molecular dynamics simulations to understand protein–ligand interactions and guide structure-based optimization. We also employ computational approaches to evaluate ADMET properties, enabling early identification of compounds with favorable pharmacokinetic and safety profiles.
By combining AI-guided design with experimental validation, we aim to accelerate the discovery of novel chemical scaffolds and improve the efficiency of medicinal chemistry campaigns.
2. Discovery of First-in-Class Small-Molecule Drug Candidates
A central goal of our laboratory is to discover first-in-class small-molecule drug candidates with demonstrated in vivo efficacy. Our approach integrates high-throughput screening, structure-based drug design, medicinal chemistry, and pharmacological characterization through iterative cycles of design, synthesis, and biological evaluation.
Using this strategy, our laboratory has discovered multiple classes of inhibitors targeting therapeutically important proteins. Representative examples include SARS-CoV-2 papain-like protease (PLpro) inhibitors, enterovirus D68 2A protease inhibitors, 3C protease inhibitors, 2C protein inhibitors, and VP1 capsid inhibitors. These studies have yielded potent antiviral scaffolds and provided key insights into the structural and mechanistic basis of inhibitor binding.
In addition to antiviral targets, we are also developing small-molecule modulators of cancer-related proteins, with the goal of creating chemical probes that enable mechanistic studies and future therapeutic development.
3. Development of Novel Covalent Warheads for Targeted Cysteine Labeling
Many therapeutically important proteins contain reactive cysteine residues that can be targeted by covalent inhibitors. Covalent inhibition can provide enhanced potency, prolonged target engagement, and improved pharmacodynamic properties.
Our laboratory develops new electrophilic warheads and covalent chemistries for selective cysteine targeting. Examples include dihaloacetamide- and trihaloacetamide-containing SARS-CoV-2 main protease inhibitors and fumaramide-containing papain-like protease inhibitors, which expand the repertoire of covalent inhibitor scaffolds for antiviral drug discovery. Through structural and mechanistic studies, we aim to develop covalent inhibitors with improved selectivity and pharmacological properties for both antiviral and cancer-related targets.
4. Targeted Protein Degradation as a New Therapeutic Modality
Targeted protein degradation has emerged as a powerful strategy for drug discovery. PROTACs (proteolysis-targeting chimeras) recruit cellular E3 ligases to induce degradation of disease-relevant proteins rather than simply inhibiting their activity.
Our laboratory is exploring PROTAC technology as a next-generation therapeutic strategy, particularly for targets that are difficult to inhibit using conventional small molecules. In antiviral applications, targeted degradation may provide a higher genetic barrier to drug resistance. As an example, we recently designed VP1-targeting PROTAC molecules that induce degradation of the viral capsid protein and retain antiviral activity against resistance mutations.
5. Prediction and Experimental Validation of Drug Resistance
Drug resistance is a major challenge in both antiviral therapy and targeted cancer treatments. Mutations that reduce drug binding can rapidly compromise therapeutic efficacy.
Our research integrates structural biology, medicinal chemistry, and experimental virology to predict and validate resistance mutations. Using structure-based approaches, we have identified key resistance hotspots for SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) inhibitors, enabling the prediction of clinically relevant resistance mutations. These studies guide the design of next-generation inhibitors with improved resistance profiles.
Understanding resistance mechanisms also provides rigorous evidence of on-target drug activity, strengthening target validation and informing the design of more durable therapeutics.
For representative publications and detailed studies, please visit our publications page.