Physical chemistry chemical physics : PCCP
July 1, 2026
W S Clemente Junior, K S Bezerra, E G C Matias et al.
Depression is a major global health problem, and the serotonin 5-HT2A receptor is a key target for psychoactive drugs. This computational study examined how four ligands—serotonin, psilocybin/psilocin, LSD, and lumateperone—bind to the receptor. Using molecular fragmentation and density functional theory calculations, the total interaction energies ranged from -35.38 to -71.98 kcal/mol. Key amino acids Asp155, Phe339, Leu229, and Val366 acted as structural anchors in the binding pocket. Different parts of the ligands showed distinct interaction patterns. The findings provide a detailed energetic map of ligand recognition that may aid the rational design of new serotonergic drugs.
Physical chemistry chemical physics : PCCP
September 18, 2025
Vito F Palmisano, Claudio Agnorelli, Shirin Faraji et al.
A new photoswitchable compound, PQ-azo-N,N-DMT, was computationally designed to improve upon an earlier version. It binds tightly to the 5-HT2A receptor, maintains key interactions similar to LSD, shows good membrane permeability, and absorbs red-shifted light for visible-spectrum photocontrol. This offers precise spatio-temporal control over receptor activation, which could help clarify the role of hallucinatory effects in antidepressant drug development.
Physical chemistry chemical physics : PCCP
January 21, 2021
Katherine J Schultz, Sean M Colby, Yasemin Yesiltepe et al.
Generative deep learning models can design new drug-like compounds that block the N-methyl d-aspartate receptor (NMDAR), a target for neurological diseases like Parkinson's and Alzheimer's, though some existing NMDAR antagonists cause dissociative effects and have been used to create illicit drugs. The study created a library of experimentally validated NMDAR PCP-site antagonists and applied ligand- and structure-based assessment techniques to deep learning-generated compounds. Twelve candidate antagonists not found in existing chemical databases were identified, but synthesis and experimental validation are still needed.