Ultra-large-scale docking, sometimes abbreviated as Ultra-LSD, is an ultra-large-scale approach to protein–ligand docking and

virtual screening Virtual screening (VS) is a computational technique used in drug discovery to search libraries of small molecules in order to identify those structures which are most likely to bind to a drug target, typically a protein receptor (biochemistry), r ...

. It employs molecular docking campaigns against libraries of millions or billions of

chemical compound A chemical compound is a chemical substance composed of many identical molecules (or molecular entities) containing atoms from more than one chemical element held together by chemical bonds. A molecule consisting of atoms of only one element ...

s to discover new

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

s. The virtual screening phase identifies potential high-

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

s and then selected promising compounds are synthesized and further evaluated in the

laboratory A laboratory (; ; colloquially lab) is a facility that provides controlled conditions in which scientific or technological research, experiments, and measurement may be performed. Laboratories are found in a variety of settings such as schools ...

, including in terms of properties like functional activity and

selectivity Selectivity may refer to: Psychology and behaviour * Choice, making a selection among options * Discrimination, the ability to recognize differences * Socioemotional selectivity theory, in social psychology Engineering * Selectivity (radio), a ...

. The purpose of Ultra-LSD is to discover novel chemical scaffolds for ligands of molecular targets. Ultra-LSD was developed by Brian Shoichet and John Irwin at the

University of California, San Francisco The University of California, San Francisco (UCSF) is a Public university, public Land-grant university, land-grant research university in San Francisco, California, United States. It is part of the University of California system and is dedic ...

, Bryan L. Roth at

University of North Carolina at Chapel Hill The University of North Carolina at Chapel Hill (UNC, UNC–Chapel Hill, or simply Carolina) is a public university, public research university in Chapel Hill, North Carolina, United States. Chartered in 1789, the university first began enrolli ...

, and other colleagues, and was first described in 2019. The researchers have conducted Ultra-LSD campaigns against a variety of targets, including the

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

5-HT_2A receptor, the

melatonin receptor Melatonin receptors are G protein-coupled receptors (GPCR) which bind melatonin. Three types of melatonin receptors have been cloned. The MT1 (or Mel1A or MTNR1A) and MT2 (or Mel1B or MTNR1B) receptor subtypes are present in humans and other ...

s, the

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

D₄ receptor, and the serotonin 5-HT_5A receptor, among others. Some of these studies have notably employed

AlphaFold2 AlphaFold is an artificial intelligence (AI) program developed by DeepMind, a subsidiary of Alphabet Inc., Alphabet, which performs Protein structure prediction, predictions of protein structure. It is designed using deep learning techniques. Alp ...

-generated models of folded receptor structures for molecular docking with ligands. The aim of the serotonin 5-HT_2A receptor Ultra-LSD campaign was to identify novel serotonin 5-HT_2A receptor

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

s, including non-

hallucinogen Hallucinogens, also known as psychedelics, entheogens, or historically as psychotomimetics, are a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mo ...

psychoplastogen Psychoplastogens, also known as neuroplastogens, are a group of Small molecule#Drugs, small molecule drugs that produce rapid and sustained effects on neuronal structure and function, intended to manifest therapeutic benefit after a single admin ...

s for potential medical use as well as

serotonergic psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

s. In 2021, it was reported that the serotonin 5-HT_2A receptor ULTRA-LSD campaign had computationally screened 11billion compounds of a library of more than 34billion compounds. It was hoped that the project would identify numerous new structural scaffolds of psychedelics. The first findings of the campaign were published in 2022. The project led to the identification of novel serotonin 5-HT_2A receptor agonists including the non-hallucinogenic G_q-biased agonist (''R'')-69, the selective serotonin 5-HT_2A receptor agonist Z3517967757, and the

β-arrestin Arrestins (abbreviated Arr) are a small family of proteins important for regulating signal transduction at G protein-coupled receptors. Arrestins were first discovered in the late '80s as a part of a conserved two-step mechanism for regulatin ...

- biased serotonin 5-HT_2A receptor agonist RS130-180, among other compounds. The project received a US$27million grant from the

Defense Advanced Research Projects Agency The Defense Advanced Research Projects Agency (DARPA) is a research and development agency of the United States Department of Defense responsible for the development of emerging technologies for use by the military. Originally known as the Adva ...

(DARPA) to develop novel

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

s. The serotonin 5-HT_2A receptor campaign was featured by Hamilton Morris in 2021 in the final episode of his TV show '' Hamilton's Pharmacopeia''. Ultra-LSD campaigns generally make use of the ZINC database, a free and publicly available curated library of billions of compounds for virtual screening that was developed by Irwin and Schoichet. ZINC was first made available in 2005 and has grown in size exponentially over time, from hundreds of thousands of compounds at launch to billions of compounds in 2022.

References

{{Reflist

External links

ZINC - Official website
Computational chemistry Drug discovery Molecular modelling