References

1. Langlitz, Nicolas (2024). "Psychedelic innovations and the crisis of psychopharmacology". BioSocieties. 19 (1): 37–58. doi:10.1057/s41292-022-00294-4. ISSN 1745-8552. In the 2010s, computational pharmacologists began to collaborate with software developers on technologies that allow to design new drugs in silico. In 2019, pharmaceutical chemist Brian Shoichet announced that one of the bubbles constraining novel drug discovery had popped (University of California, San Francisco 2019). [...] Instead of screening drug libraries physically, Lyu et al. (2019) had created an ultra-large virtual library of 170 million compounds, which a computer simulation rotated and adjusted to identify those compounds that might bind to a particular receptor or some other target. [...] In 2020, Shoichet's laboratory at the University of California, San Francisco, provided a proof of concept that in silico drug design allowed to discover new drugs. Looking for a medication to treat sleep disorders and jet lag, they searched the virtual library for molecules that specifically docked to one of the two mammalian melatonin receptors called MT1. They ran computer simulations of 72 trillion drug-receptor interactions and eventually identified 40 potential drugs. Employing another recently invented technology, the Ukrainian company Enamine was then able to synthesize 38 of these molecules by combining prefabricated chemical building blocks with one another (at a cost of approximately $100 per molecule). At that point, in vitro and in vivo testing allowed Shoichet's group to identify those drugs that actually bound to MT1 and to establish their behavioral effects in mice (Stein et al. 2020). The chemical scafolds of these molecules were unrelated to known melatonin receptor ligands. [...] In light of the promising results of psychedelic-assisted psychotherapy, Brian Roth's laboratory at the University of North Carolina at Chapel Hill received a $27 million grant from the US Department of Defense to use the tools of computational pharmacology to develop drugs that have the therapeutic but not the psychedelic effects of 5-HT2a agonists like LSD and psilocybin. [...] One major reservation regarding Roth's approach to drug discovery was raised in a personal communication with Hamilton Morris: "Roth's ULTRA-LSD* technique is designed to characterize high affinity ligands, which are then further screened for functional activity and receptor selectivity. Neither affinity nor selectivity are in and of themselves a determinant of therapeutic efficacy. [...] concepts like affinity and selectivity, while extremely valuable in pharmacology research, are not immediately applicable to a therapeutic domain especially in the realm of psychedelics."
2. Weiler, Nicholas (6 February 2019). "'Virtual Pharmacology' Advance Tackles Universe of Unknown Drugs". ‘Virtual Pharmacology’ Advance Tackles Universe of Unknown Drugs. Retrieved 6 June 2025. Scientists at UC San Francisco, in collaboration with colleagues at the University of North Carolina (UNC), have developed the world's largest virtual pharmacology platform and shown it is capable of identifying extremely powerful new drugs. The platform, soon to contain over a billion virtual molecules never before synthesized and not found in nature, is poised to dramatically change early drug discovery and send waves through the pharmaceutical industry, the authors say. [...] Now Brian Shoichet, PhD, and John Irwin, PhD — a professor and adjunct associate professor of pharmaceutical chemistry, respectively, in UCSF's School of Pharmacy — have begun to crack this problem through a collaboration with a remarkable chemical supplier based in Ukraine, as described in a study published February 6, 2019 in Nature. [...] Irwin and Shoichet have partnered with Enamine to begin incorporating its vast virtual catalogue into their free public drug discovery database — called ZINC — which currently contains over 750 million compounds and is constantly growing as Enamine and other suppliers add new building-blocks and chemical reactions. [...] "Our platform can now screen 100 times more molecules than are available in most drug screening libraries, with far more diversity in the molecules screened. Soon it will be able to screen 1000 times more," Irwin said. "People are going to have access to a lot of new chemistry that no one has looked at before."
3. McClure-Begley TD, Roth BL (June 2022). "The promises and perils of psychedelic pharmacology for psychiatry". Nat Rev Drug Discov. 21 (6): 463–473. doi:10.1038/s41573-022-00421-7. PMID 35301459. Discovering new chemical matter with beneficial actions at 5-HT2A receptors will likely be accelerated by ultra-large-scale computational approaches130. In proof-of-concept studies we and others have shown that the ultra-large-scale docking of in silico enumerated molecules can afford the discovery of potent and selective compounds with biased signalling properties at prototypical G protein-coupled receptors (GPCRs)130,131. One can thereby envision a similar strategy aimed at 5-HT2A receptors where, ultimately, billions of compounds might be interrogated computationally at relevant 5-HT2A receptor complexes.
4. Bryan L. Roth (1 August 2019). VEGAS and ULTRA-L.S.D.: Two New Technologies to Illuminate GPCR Structure and Function (PDF). Chemistry and Pharmacology of Drug Abuse (CPDA) Conference 2019.
5. Lyu J, Wang S, Balius TE, Singh I, Levit A, Moroz YS, O'Meara MJ, Che T, Algaa E, Tolmachova K, Tolmachev AA, Shoichet BK, Roth BL, Irwin JJ (February 2019). "Ultra-large library docking for discovering new chemotypes". Nature. 566 (7743): 224–229. Bibcode:2019Natur.566..224L. doi:10.1038/s41586-019-0917-9. PMC 6383769. PMID 30728502.