Discovery of novel modulators targeting human TRPC5: Docking-based virtual screening, molecular dynamics simulation...

Area of Science:

• Molecular biology and pharmacology
• Computational drug discovery
• Ion channel research

Background:

• Canonical transient receptor potential channel 5 (TRPC5) is implicated in various physiological and pathological processes, including CNS disorders, cardiovascular diseases, and cancer.
• Limited understanding of TRPC5 function at cellular and organismic levels necessitates the identification of novel modulators.
• Efficient TRPC5 channel modulators are crucial for further research into TRPC5's biological roles.

Purpose of the Study:

• To identify novel small molecule modulators of human TRPC5 (hTRPC5) through virtual screening.
• To evaluate the binding affinity and potential therapeutic value of identified compounds.
• To provide lead compounds for further investigation of TRPC5-associated diseases.

Main Methods:

• Virtual screening of 212,736 compounds from the Specs database using homology modeling of hTRPC5 structure.
• Application of Lipinski's and Veber's rules, ADMET, and PAINS filters for initial compound selection.
• Multi-software docking, cluster analysis, and interaction analysis to identify potential active candidates.
• All-atom molecular dynamics (MD) simulations of selected hits with hTRPC5 to assess binding stability and interactions.

Main Results:

• Virtual screening identified 20 potential active candidates with novel skeletons.
• Four selected compounds (Hits) exhibited appreciable binding affinity with hTRPC5.
• MD simulations indicated that the binding of the 4 Hits induces minor structural changes and stabilizes the hTRPC5 structure.
• Key residues involved in stabilizing the hTRPC5-ligand complex were identified through decomposition free energy analysis.

Conclusions:

• The identified 4 Hits represent potential modulators of hTRPC5.
• These compounds may serve as valuable lead structures for the development of novel therapeutics targeting hTRPC5-associated diseases.
• Further experimental validation is warranted to confirm the efficacy and safety of these potential modulators.