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Finding new drugs using computational chemistry and AI machine-learning tools
Imagine trying to find the right key to open a lock from a pile of millions – this is akin to the early stages of drug discovery. Recent advancements in computational methods are accelerating and transforming this process.
The Computational Drug Discovery Process
- Target Identification: We begin by selecting a protein with significant biological relevance and potential for drug interaction, such as the 5-HT2A receptor.
- Structural Analysis: Next, we determine the 3D structure of this receptor, the ‘lock', using experimental methods such as X-ray crystallography or cryo-electron microscopy, and create a computational model of it.
- Virtual Screening: Here, algorithms comb through extensive chemical libraries, containing millions of compounds, to identify potential ligands, or 'keys'.
- Molecular Docking: This involves sophisticated simulations to model how these ligands interact with the receptor.
- Predictive Modeling: Techniques like quantum mechanics refine our understanding of ligand-receptor interactions.
- Experimental Confirmation: Computational methods only provide predictions. Finally, promising ligands are synthesized and their activity at real receptors is tested in the lab to confirm computational predictions.
Understanding Receptors Dynamics
Proteins, including receptors, are complex molecules composed of amino acid chains that fold into unique 3D structures – like kinetic protein origami. The sequence of amino acids dictates how the protein will fold and the shape of a protein determines its function in the body. Receptors are dynamic and their confirmation change based on internal and external interactions.
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Using Machine Learning to Discover Psychedelics
A recent preprint has made headlines for using AlphaFold, the artificial intelligence tool that predicts protein structures, to identify hundreds of thousands of potential new psychedelics. AlphaFold uses deep learning algorithm that analyzes amino acid sequences of known protein structures to determine the distances and angles between residues and model their 3D spatial arrangement.
In this study, hundreds of millions of potential drugs were screened against a traditional experimental structure of the 5-HT2A receptor and a structure predicted by AlphaFold. Then, hundreds of the most promising compounds from both campaigns were synthesised and experimentally evaluated for their activity against the real receptors.
The findings:
- The receptor structures predicted by AlphaFold and those determined experimentally differed considerably.
- Both approaches yielded completely different drug candidates.
- Surprisingly, the ‘hit rates’ — the proportion of compounds that effectively altered protein activity — were nearly identical for both groups.
- Notably, the most potent 5HT2A agonists were identified using AlphaFold’s predicted structures.
Limitations and Future Prospects
While AlphaFold's predictions have shown promise, they are not universally applicable. In most cases, traditional experimentally-determined structures have been more reliable for identifying potential drugs. However, AI models like AlphaFold offer additional tools for drug discovery, potentially uncovering drugs overlooked by conventional methods.
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Psylo Discovers Novel 5-HT2A Agonists
Using computational modelling, Psylo identified thousands of potential ligands for the 5-HT2A receptor. Through rigorous experimental validation, we have not only confirmed the existence of novel ‘psychedelic’ compounds but also uncovered a completely unique chemical scaffold. This exciting discovery has laid the foundation for the development of our innovative 500X series.
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Psychedelic Clinical Research
- Psilocybin Therapy for Bipolar II Depression | Psilocybin combined with psychotherapy effectively and safely treated depressive episodes bipolar II disorder, with most patients in remission at 3 and 12 weeks post-treatment – an open-label, nonrandomized controlled trial (N=15) | JAMA Psychiatry
- Analysis of Antidepressant Clinical Trials | Most RCTs focused only on clinical remission, with a low emphasis on functional remission and relapse prevention, and used stringent eligibility criteria that often excluded older patients and those with comorbid anxiety disorders – a systematic analysis of 122 RCTs from 2008-2022 | Psychiatry Res
- LSD and Neural Complexity Effects | Low doses of LSD, but not THC or methamphetamine, increased neural complexity without correlating to altered consciousness – placebo-controlled, within-subject clinical trial with EEG measurements (N = 73) | Neuropsychopharmacology
- Expectancy in Psilocybin vs. Escitalopram | Patients had higher pre-trial expectancy for psilocybin compared to escitalopram, but only expectancy for escitalopram predicted its therapeutic outcomes in a randomized head-to-head trial for major depressive disorder (N = 55). Pre-treatment suggestibility was associated with response to psilocybin but not escitalopram. Psilocybin therapy may be less affected by expectancy biases than previously thought, and individuals with high suggestibility may be more responsive to psilocybin treatment | Psychol Med
- Psilocybin Therapy for Cancer-Related Depression | Phase 2 trial with 30 cancer patients shows psilocybin-assisted therapy is safe and potentially effective in treating major depressive disorder, with 80% of participants showing a sustained response and 50% achieving full remission of depressive symptoms at week 1, lasting for 8 weeks. | Cancer
- Predicting Antidepressant Response via EEG | EEG data predicted antidepressant treatment outcomes in MDD patients, successfully distinguishing between sertraline and placebo responses (N=221), advance the neurobiological understanding of antidepressant responses | J Affect Disord
- The Link Between Psychedelics and Psychosis | Psychedelic use did not affect psychotic symptoms during the a two-month period unless there was a personal or family history of bipolar or psychotic disorders, found a longitudinal study if US and UK adults (N=9,732). The number of psychotic symptoms increased with a personal or family history of bipolar disorder and decreased with a personal (but not family) history of psychotic disorders | J Affect Disord
- Interactions between Psychedelics and Antidepressants | A survey study comparing psychedelic experiences in individuals on serotonergic antidepressants vs. those not on medication (N=161). Participants not on antidepressants experienced more intense subjective effects of psychedelics, but both groups showed similar improvements in well-being and depressive symptoms. | J Psychopharmacol
- MDMA's Impact on Social Feedback Responses | MDMA increased positive responses to social feedback, compared to placebo and methamphetamine in a placebo-controlled, crossover clinical trial (N=36). These findings indicate a mechanism through which MDMA could facilitate social connection| J Psychopharmacol
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Psychedelic Preclinical Research
- Deciphering 5-HT2A Psychedelic Pathways | Study develops selective ligands to understand which signaling pathways of the 5-HT2A receptor are associated with psychedelic effects. 5-HT2A-Gq, but not 5-HT2A-β-arrestin2, recruitment predicts the psychedelic potential of compounds. A threshold level of Gq activation is required to induce psychedelic-like effects. Disrupting Gq-PLC signaling attenuates, while β-arrestin-biased 5-HT2A agonists can block, psychedelic effects. These findings aid in the development of non-psychedelic 5-HT2A agonists. | Nat Commun
- Psychedelics in Depression, 5-HT2A and Beyond | 5-HT2A agonists, DOI, psilocybin, and lisuride, indued antidepressant-like effects in a chronic despair mouse model. DOI and lisuride effects were absent in 5-HT2A knock-out mice, while psilocybin remained effective, suggesting that there may be non-hallucinogenic pathways for treating MDD | Neuropsychopharmacology
- Psilocybin's Effects on Zebrafish Behavior | Using larval zebrafish, the study finds psilocybin increases exploration and reduces stress-induced swim irregularities, differing from SSRIs and mirroring ketamine's effects | Mol Psychiatry
- Psilocybin for Chronic Pain in Rats | Study demonstrates that a single intravenous dose of psilocybin can effectively reduce chronic pain symptoms (mechanical hypersensitivity) in a rat model of chronic pain, suggesting potential therapeutic use in pain management. | Curr Biol
- Psilocybin Effects on Alcohol Dependence in Rats | Psilocybin induced widespread decreases in functional connectivity and increased connectivity between serotonergic core regions and cortical areas in a pharmaco-fMRI study on healthy and alcohol-dependent rats. Interestingly, psilocybin’s effect were blunted in alcohol-dependent rats, correlating with alcohol relapse intensity, and suggesting limited efficacy for severe alcohol dependence | Transl Psychiatry
- Psychedelics' Anti-Inflammatory Mechanisms | Study compares two 5-HT2A receptor agonists in a mouse model of asthma, revealing differing anti-inflammatory effects and highlighting suppression of arginase 1 as a key mechanism in psychedelic-induced anti-inflammation | ACS Pharmacol Transl Sci
- Psychedelic Activity of Norpsilocin Analogues | Investigation of norpsilocin derivatives reveals that certain structural modifications, like extending the N-methyl group, can induce psilocin-like psychedelic activity, highlighting structural factors critical for psychedelic effects. | ACS Chem Neurosci
- Ibogamine Derivative is Anxiolytic via 5-HT2A | DM506, a non-hallucinogenic compound derived from ibogamine, induced anxiolytic and sedative effects in mice via 5-HT2A receptor activation and without inducing hallucinogenic effects; presenting a non-hallucinogenic candidate for anxiety treatment | Eur J Pharmacol
- Psilacetin as an Alternative to Psilocybin | Psilacetin (4-AcO-DMT) converts to psilocin in mice but only yields about 70% of the psilocin exposure that psilocybin does | Front Psychiatry
- Benzofuran Derivatives and MDMA-like Effects | Novel benzofuran were efficacious monoamine releasers, with varied releasing activity at serotonin, norepinephrine, and dopamine transporters, and dose-dependent MDMA-like behavioral effects in rats. These compounds may produce compounds with MDMA-like properties with possibly lower risks | J Pharmacol Exp Ther
- [Preprint] Psilocybin for Anorexia in Rats | Psilocybin improved body weight maintenance and cognitive flexibility in a rat model of activity-based anorexia, with 5-HT1A antagonism negating these cognitive effects | bioRxiv
- [Preprint] AlphaFold2 Aids Ligand Discovery | AlphaFold2 models, which predict the 3D structure of the 5-HT2A receptor structure, were effective at discovering new 5-HT2A agonists. Structure-based ligand hit rates were similar between AlphaFold2 models and experimentally derived structures. However, the most potent, subtype-selective agonists were discovered by docking against the AlphaFold2 model, not the experimental structure | bioRxiv
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Psychedelic Reviews and Commentaries
- Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants – Chem Rev | This Perspective provides an overview of the structure-activity relationships of existing 5-HT2AR agonists based on their chemical classifications and discusses recent advancements in understanding their molecular pharmacology at a structural level.
- The Effects of Psychedelics on Neuronal Physiology - Annu Rev Physiol | This review explores the unique impact of psychedelics on neuronal physiology, describing their acute effects on neurotransmission and long-lasting effects on neuroplasticity, suggesting potential opportunities for developing compounds with optimized safety and efficacy profiles.
- Do the therapeutic effects of psilocybin involve actions in the gut? - Trends Pharmacol Sci | This article explores the potential role of psilocybin's peripheral actions in the gut, including its impact on serotonin receptors and the gut-brain axis, in contributing to rapid and long-term therapeutic effects for mental health conditions, suggesting the need for a greater understanding of these mechanisms for targeted drug development.
- An integrative view on the cell-type-specific mechanisms of ketamine's antidepressant action - Trends Neurosci | This review discusses the evolving use of ketamine as an antidepressant and examines preclinical studies that investigate cell-type-specific mechanisms underlying ketamine's effects on behavior and synapses, emphasizing the importance of such approaches in understanding its therapeutic effects.
- Psychedelics for acquired brain injury: a review of molecular mechanisms and therapeutic potential - Mol Psychiatry | This narrative literature review explores the potential of psychedelics as a therapeutic intervention for acquired brain injury (ABI) by examining their neurochemical properties, including their effects on serotonin receptors, sigma-1 receptors, and neurotrophic signaling, which suggest potential benefits in managing ABI, although further research is needed to understand their mechanisms of action and effectiveness in ABI treatment.
- A molecular perspective on mGluR5 regulation in the antidepressant effect of ketamine - Pharmacol Res | This review explores the role of metabotropic glutamate receptor 5 (mGluR5) in the antidepressant effects of ketamine, highlighting the potential molecular mechanisms underlying this relationship and proposing a possible link between NMDAR inhibition and mGluR5 modulation.
- The mechanistic divide in psychedelic neuroscience: An unbridgeable gap? - Neurotherapeutics | This perspective discusses the current divide in explanatory models of psychedelic drug action across different levels of inquiry and emphasizes the need for innovative methods and collaboration to bridge this gap for a comprehensive understanding of the therapeutic potential of psychedelics.
- The Psychedelic Future of Post-Traumatic Stress Disorder Treatment - Curr Neuropharmacol | This review discusses the potential of psychedelic compounds, including psilocybin, LSD, DMT, MDMA, and ketamine, in the treatment of PTSD and trauma-related disorders, considering their history of use, effects, pharmacology, safety, and future directions for psychiatric applications.
- Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms – Neuropsychopharmacology | This review explores the rapid antidepressant effects of ketamine, its synaptic and circuit mechanisms, and how these insights can pave the way for more effective treatments for neuropsychiatric disorders.
- Making Sense Of Psychedelics In The CNS - Int J Neuropsychopharmacol | This review provides a historical overview of psychedelics, discusses current techniques for studying them from a pharmacological perspective, and highlights gaps in the field and potential avenues for further research in understanding their physiological changes and therapeutic capabilities.
- Microdosing psychedelics: Current evidence from controlled studies - Biol Psychiatry Cogn Neurosci Neuroimaging | This review focuses on controlled studies evaluating the practice of microdosing psychedelic drugs, particularly LSD, and finds that low doses of LSD are relatively safe and produce acute behavioral and neural effects in healthy adults.
- 5-MeO-DMT: An atypical psychedelic with unique pharmacology, phenomenology & risk? - Psychopharmacology | This article explores the unique pharmacology and effects of 5-MeO-DMT, suggesting that its therapeutic mechanism may involve temporary epileptiform activity, potentially similar to electroconvulsive therapy, and calls for further research on its mechanisms.
- Psychedelics, epilepsy, and seizures: a review - Front Pharmacol | This review highlights that all clinical trials examining psychedelics have excluded any individual with a past or current history of seizures, without definitive evidence demonstrating that psychedelics induce seizures. It highlights cases of seizure induction or seizure remission following psychedelic use, and proposes future research directions in this area.
- [Patent Highlight] Perceptual Modifying Compounds and Their Potential Therapeutic Applications in Neuropsychiatric Disorders - ACS Med Chem Lett | This Patent Highlight explores the potential therapeutic use of psychedelic compounds, such as ketamine, LSD, and analogs, for neuropsychiatric disorders by discussing their mechanisms of action, including synaptic plasticity and prefrontal cortex regulation, and emphasizes their promise in addressing conditions like depression, anxiety and addiction.
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Psychedelic Clinical Trials Update
A round-up of the latest registered clinical trials investigating psychedelics:
- DMT | Acute Pain | Acute Analgesic Effects of DMT on Experimentally Induced Pain in Healthy Participants (DPS) - NCT06180759
- Esketamine | Chronic Pain Due to Endometriosis | Esketamine as Treatment for Chronic Pain Due to Endometriosis: a RCT Study (EASYlight) - NCT06161805
- Esketamine | Rett Syndrome | An Exploratory Trial of Esketamine for the Treatment of Rett Syndrome - NCT06199700
- Ketamine | Depression and PTSD with TBI | Examining the Efficacy and Safety of Subanesthetic Ketamine on Depression and Post-traumatic Stress Among Veterans With Mild and Moderate Traumatic Brain Injury - NCT06228391
- Ketamine | Parkinson's Disease | Examining Ketamine Effects on Depression, Neuroplasticity, and Inflammation in Veterans With Parkinson's Disease - NCT06231563
- MDMA | Post-Traumatic Stress Disorder | Epigenetic Regulation of Stress-related Genes in Relation to MDMA-Assisted Psychotherapy Treatment for Post-Traumatic Stress Disorder - NCT06189027
- Psilocybin | Synaptic Density in Opioid Use Disorder | Exploration of Synaptotrophic Effects of Psilocybin in Opioid Use Disorder (OUD) – NCT06160284
- Psilocybin + Cognitive Behavior Therapy | Tobacco Use Disorder | 5-HT2A Agonist Psilocybin in the Treatment of Tobacco Use Disorder - NCT05452772
- Psilocybin With Psychological Support | Treatment-resistant Depression | Effects of Psilocybin With Psychological Support on Anhedonia in Treatment-resistant Depression: a Randomized Controlled Pilot Trial - NCT06230757
- Psilocybin-Assisted Therapy | Cannabis Use Disorder | Psilocybin-assisted-psychotherapy in the Treatment of Cannabis Use Disorder: A-Proof-of-Concept Study (PSI_CUD) - NCT06225232
- Psilocybin-Assisted Therapy | Depression and/or Anxiety in Advanced Cancer | TRIP - TReatment to Improve Depression and/or Anxiety Using Psilocybin-Assisted Psychotherapy in Patients With Advanced Cancer on Maintenance Therapy - NCT06200155
- Psilocybin-Assisted Therapy | Severe Alcohol Use Disorder | Psilocybin-Assisted Therapy for Severe Alcohol Use Disorder: Feasibility, Clinical Efficacy & (Neuro)Cognitive Mechanisms - NCT06160232
- Psychedelic-mimicking VR Therapy | Clinical Depression | Effect of Psychedelic VR-augmented Therapy [no drug; VR experience mimics phenomenological components of psychedelic experience] on Patients With Clinical Depression - NCT06174285
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Sam, Krista, and Josh spent a week together in the Bay Area at JPM. Lots of productive meetings with partners, investors, collaborators, and friends.
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Psylo and advisors at the American College of Neuropsychopharmacology (ACNP)
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Are we on the brink of a mental health revolution? Joshua Ismin CEO of Psylo, believes so. Josh’s TEDxSydney was promoted across the TEDx International channels in December!
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Psylo’s Head of Communications, Dr Dilara Bahceci wrote an article for Psychedelic Alpha about the health inequities with accessing ketamine antidepressants.
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