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.
Research (Wash D C)
October 4, 2024
Miyuan Zhang, Yibo Wang, Tian-Ming Gao et al.
10 citations
Psychedelics alter sensory perceptions, disrupt self-referential thought, and can catalyze spiritual and existential experiences. As research advances, these substances are being integrated into therapeutic settings, challenging existing psychiatric models and offering new insights into consciousness and mental health. This emerging paradigm calls for careful regulation and ethical considerations, promising a more holistic approach to mental health disorders.
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.
Natl Sci Rev
April 25, 2025
Yibo Wang, Xiaohui Wang
2 citations
The article proposes that entheogens—plant-based psychoactive substances used historically in spiritual and healing rituals—may be understood through the lens of evolutionary medicine as treatments for neuropsychiatric disorders. It argues that these compounds can address deep-seated brain mechanisms underlying conditions like depression and anxiety by resetting maladaptive neural pathways and promoting psychological flexibility. The text suggests that modern mental health challenges arise partly from mismatches between ancestral environments and contemporary lifestyles, and that entheogens offer a novel paradigm for healing by reconnecting individuals with evolved neurobiological processes. The authors indicate that this evolutionary perspective could guide clinical use and improve well-being.
Proceedings of the National Academy of Sciences
June 24, 2026
Yibo Wang, H Wang, C T Lin et al.
Natural hallucinogenic compounds like mescaline and psilocybin evolved independently across plants, fungi, and animals through a 'building-block' biosynthetic logic that repurposes primary metabolism. These molecules likely function as defensive agents or manipulators of herbivore and pollinator behavior, not primarily for human psychoactivity. Endogenous mammalian tryptamines appear to serve cytoprotective and stress-response roles via sigma-1 receptors, not hallucinogenic functions. Across kingdoms, these compounds converge on conserved neural targets such as serotonergic systems, making human psychoactivity an evolutionary by-product of molecules selected for ecological interactions with animals sharing deeply conserved receptor architectures.
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.