Advanced science (Weinheim, Baden-Wurttemberg, Germany)
April 2, 2025
Cong Lin, Xiaoxuan Zhou, Mingqi Li et al.
14 citations
In a mouse model of inflammation-induced depression, S-ketamine (S-KET) reduced depressive-like behaviors and lowered pro-inflammatory factors in the medial prefrontal cortex, while R-ketamine (R-KET) did not. S-KET bound directly to the protein SIRT2 at the Q167 residue, enhancing its interaction with NF-κB subunit p65, which reduced acetylation and suppressed pro-inflammatory gene expression. Experiments using RNA interference, a SIRT2 inhibitor (AK-7), and pharmacological blockade confirmed that SIRT2 is essential for these effects. The findings indicate that SIRT2 mediates the therapeutic actions of S-KET, suggesting a target for treating inflammation-associated depression.
European journal of medicinal chemistry
January 5, 2025
Miyuan Zhang, Yuefeng Yang, Zhishuai Yang et al.
10 citations
The position of the hydroxyl group on the indole ring of psilocin analogs determines their ability to activate the 5-HT2A receptor and produce psychedelic-like effects. Analogs with the hydroxyl group at the 4th or 5th position (psilocin and bufotenine) show significantly higher agonistic activity and head-twitch responses than those with the group at the 6th or 7th position. Computer simulations reveal that the 4- and 5-position analogs form a crucial hydrogen bond with residue L229 and a stable salt bridge and hydrogen bond with residue D155, guiding them into the binding site. Analogs lacking these interactions fail to reach the orthosteric site and have poor receptor activity.
ACS pharmacology & translational science
July 11, 2025
Cong Zhang, Yibo Wang, Xiaohui Wang
2 citations
Neuropsychiatric disorders arise from disruptions in brain network dynamics that fall along a spectrum from order to complexity to chaos. Psychedelics may work therapeutically by increasing neural entropy, breaking maladaptive patterns, and enabling network reorganization. This framework focuses on dynamic remodeling of the brain's connectome rather than static molecular fixes, proposing that controlled neural destabilization and reconnection offers a new treatment strategy for psychiatric and neurological conditions.
Expert opinion on drug discovery
May 1, 2026
Cong Zhang, Pu Jiang, Yibo Wang et al.
Psychedelics hold therapeutic promise for central nervous system disorders but are limited by hallucinogenic side effects. Molecular dynamics simulations provide atomic-level insights into receptor interactions, helping to overcome these challenges and guide the development of safer, more effective therapies. This perspective reviews how MD simulations reveal mechanisms such as biased signaling, receptor multimerization, and lipid modulation, and discusses their role in validating cryo-EM binding sites. Challenges in force fields, structural data, and system complexity must be addressed to advance rational drug design. MD simulations are transforming psychedelic drug discovery from serendipity to precision design, with the goal of a predictive 'digital pharmacology' platform.