Dimer-interface effects on tetramer stabilization and tryptophan dynamics in allosterically modulated TPH-II

Tryptophan hydroxylase-II (TPH-II) controls the rate-limiting step of neuronal serotonin biosynthesis and plays a central role in neuropsychiatric health. As proper tetramer formation is essential for TPH-II stability and function, targeting its quaternary structure through allosteric modulation presents a promising yet still underexplored therapeutic strategy. In this study, we combined virtual screening, molecular dynamics simulations, and MMPBSA to identify ligands that bind at the interfacial A-D allosteric pocket of tetrameric human TPH-II.

All the analyzed candidates, L1-L6 maintain the compact global conformations, as supported by RMSD, RMSF, PCA, FEL, and salt-bridge analyses. MM/PBSA analysis indicated that L2 exhibited the most favorable binding energy among the studied complexes, while in silico ADMET profiling suggested that L2 and L4 possess favorable CNS-compatible pharmacokinetic properties. Together, these findings provide insight into allosteric modulation of TPH-II and identify the A-D interface as a potential regulatory region contributing to tetramer integrity and highlighting L2 may serve as a candidate scaffold for further computational and experimental investigation in TPH-II functional regulation.

The authors extend their appreciation to the Ongoing Research Funding Program (Project number ORF-2026-357, King Saud University, Riyadh, Saudi Arabia, for providing funding for this research. The authors gratefully acknowledge the Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, for providing research facilities. This research was supported by Ongoing Research Funding Program (project number ORF-2026-357), King Saud University, Riyadh, Saudi Arabia.

Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan Anisa Anjum, Sara Khan, Umar Farooq & Muhammad Naseem Khan Department of Chemistry, Pennsylvania State University, University Park, PA, 16802, USA Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, 11451, Riyadh, Saudi Arabia Department of Biochemistry College of Science, King Saud University, PO Box 22452, 11451, Riyadh, Saudi Arabia Correspondence to Sara Khan or Umar Farooq. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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