Towards high-resolution modeling of small molecule - ion channel interactions

Ion channels are critical drug targets for a range of pathologies, such as epilepsy, pain, itch, autoimmunity, and cardiac arrhythmias. To develop effective and safe therapeutics, it is necessary to design small molecules with high potency and selectivity for specific ion channel subtypes. There has been increasing implementation of structure-guided drug design for the development of small molecules targeting ion channels. We evaluated the performance of two Rosetta ligand docking methods, RosettaLigand and GALigandDock, on structures of known ligand - cation channel complexes. Ligands were docked to voltage-gated sodium (NaV), voltage-gated calcium (CaV), and transient receptor potential vanilloid (TRPV) channel families. For each test case, RosettaLigand and GALigandDock methods were able to frequently sample a ligand binding pose within 1-2 Å root mean square deviation (RMSD) relative to the experimental ligand coordinates. However, RosettaLigand and GALigandDock scoring functions ca...,
Ligand generation
Ligands were extracted as Structure Data Files (.sdf) from PubChem (Kim et al, 2023). Using the Avogadro software (Hanwell et al, 2012), each ligand structure underwent bond-correction, protonation at pH 7.4, and energy minimization using the Merck Molecular Force Field (Halgren, 1996a; b; c; Halgren and Nachbar, 1999; Halgren, 1999a; b). The resulting models were saved as Tripos Mol2 (.mol2) files. The protonation and bond order of saxitoxin and tetrodotoxin was matched to experimentally reported work (Hinman and DuBois, 2003; Thomas-Tran and Du Bois, 2016). Both experimentally resolved structures of verapamil docked to rabbit CaV1.1 were tested (Zhao et al, 2019).
Next, using Amber Tools’ Antechamber protocol, the partial atomic charge, atom, and bond type assignments for each ligand were AM1-BCC corrected (Case et al, 2021; Salomon-Ferrer, Case, and Walker, 2012; Appendix S1). AM1-BCC correction is commonly used in Rosetta-based ligand docking protocols (Smith and ..., , # Data from: Towards high-resolution modeling of small molecule - ion channel interactions

This README file was generated on 2024-05-02 by Brandon Harris and Vladimir Yarov-Yarovoy.

**GENERAL INFORMATION**

**1. Title of Dataset:** Towards high-resolution modeling of small molecule – ion channel interactions 

**2. Author Information**

            A. Principal Investigator Contact Information

             Name: Vladimir Yarov-Yarovoy         

             Institution: University of California, Davis

             Address: 1275 Med Science Drive, Davis, CA 95616-5271 USA

             Email: [[e-mail]](mailto:[e-mail])

**3. Date of data collection** (single date, range, approximate date): 2023-2024 

**4. Geographic location of data collection**: 1275 Med Science Drive, Davis, CA 95616-5271 USA

**5. Information about funding sources that supported the collection of the data**:

National Institutes of Health, Award: R61NS127285

National Institutes of Health, ...