PROJECT 2
Binding Site Mapping & In Silico Drug Screening
We locate where drugs bind to ion channels — then use that map to find new ones.
Molecular Docking
MD Simulation
In Silico Screening
THE PROBLEM
Most drugs are found without knowing where they bind.
Ion channel drugs are typically discovered through brute-force screening: test thousands of compounds, identify what blocks the channel, worry about mechanism later.
Without knowing where a drug binds or how it closes the channel, rational improvement is impossible — and off-target effects are hard to predict.
A structural map of drug-binding sites turns guesswork into design.
Our approach starts from structure.
We use computational tools — molecular docking, clustering algorithms, and molecular dynamics simulations — to map the exact pockets where drugs bind. We then validate those pockets experimentally with patch clamp electrophysiology and mutagenesis. Once we have the map, we screen natural compound libraries to find new drug candidates that fit those pockets.
OUR APPROACH
Three steps: map, simulate, screen.
We combine structural pharmacology with experimental validation. Each new channel target follows the same pipeline — and each one deepens the structural map.
Unbiased Docking
BINDING SITE MAPPING
AutoDock Vina screens the entire channel surface. A k-means clustering algorithm groups thousands of docking poses by channel geometry — identifying binding pockets without prior assumptions.
MD Simulation
MECHANISM VALIDATION
600–1,500 ns molecular dynamics trajectories with MM-PBSA energy decomposition reveal how each drug closes the channel — and which residues drive the interaction.
In Silico Screening
DRUG DISCOVERY
Natural compound libraries are screened against validated binding sites using a custom RIS (Residue Interaction Similarity) scoring function. Top hits are validated by patch clamp and calcium imaging.
PIPELINE
From channel structure to validated drug candidate.
What began with three ion channels is now a generalizable platform. Our binding site mapping pipeline and in-house in silico screening tool are designed to work across any ion channel with a known structure — enabling systematic drug-binding site identification and candidate discovery at scale.
KEY RESULTS
Three channels. Three structural discoveries.
Each channel taught us something new about how drugs bind — and gave us tools to find the next generation of candidates.
TMEM16A
PNAS 2024
Ca²⁺-activated Cl⁻ channel
Two distinct drug-binding pockets identified for the first time
Magnolol blocks the pore pocket directly; honokiol occupies a nonpore pocket and allosterically closes the channel gate. Among 17 known inhibitors, 11 are pore blockers and 6 are nonpore blockers.
TREK-2
ChemMedChem 2024
K2P potassium channel · DRG neurons
Same binding site, opposing pharmacology — explained
Alpha-mangostin and norfluoxetine both bind the fenestration site, yet one activates and one inhibits TREK-2. The difference lies in how each molecule interacts with K⁺ ions at the selectivity filter.
TRPV3
In Preparation
TRP channel · Keratinocyte
Natural compound identified as potent TRPV3 inhibitor by in silico screening
1,063 natural compounds screened using AutoDock Vina and the novel RIS scoring function. NC suppressed TRPV3 currents, cytokine release in keratinocytes, and rescued cell death in Olmsted syndrome GOF mutants.
REPRESENTATIVE PUBLICATIONS
Key papers from this program.
2025
A natural inhibitor of TRPV3 unveiled by in silico screening interferes with key steps of the pathomechanism of skin disorders
Roh JW, Van NTH, Dang H, Kim JY, Kim HJ, Lee W, Wainger BJ, Kim SJ, Gee HY, Kim WK, Nam JH (co-corresponding)
Manuscript under preparation · DOI to be assigned
Interested in this program?
Students and collaborators can learn more about our ongoing research or get in touch directly.