Dominic Meusch’s Post

"High-Throughput SFC-MS/MS Method to Measure EPSA and Predict Human Permeability" (https://lnkd.in/esSNZfTG) ❗🔬Highly recommend this recent paper to all Drug Hunters🔬❗ Yue-Ting Wang, et al. introduce a novel high-throughput (HT) method for measuring experimental polar surface area (EPSA) as a surrogate for permeability assessment, especially for compounds that do not comply with Lipinski’s Rule of 5. This method leverages supercritical fluid chromatography-tandem mass spectrometry (SFC-MS/MS) to enhance sensitivity, selectivity, and data quality while significantly reducing data acquisition time. EPSA serves as a predictor for Caco-2 cell and human intestinal permeability, offering improvements over traditional topological polar surface area (TPSA) and parallel artificial membrane permeability assays (PAMPA). This new HT-EPSA method is particularly beneficial for evaluating bRo5 compounds such as proteolysis targeting chimeras (PROTACs), cyclic peptides, and macrocycles, which require conformational flexibility and intramolecular hydrogen bonding (IMHB) to optimize solubility, permeability, and target binding. The paper highlights the utility of HT-EPSA in early-stage drug discovery for rank-ordering compounds, accelerating decision-making, and predicting in vitro and in vivo human intestinal permeability, thus offering a significant advancement for medicinal chemists working on challenging drug targets.

Studying 𝘁𝗼𝘅𝗶𝗻𝘀 is crucial for advancing our understanding of 𝗶𝗼𝗻 𝗰𝗵𝗮𝗻𝗻𝗲𝗹𝘀 and developing new drugs. Many toxins specifically target ion channels, making them invaluable tools in research and offering unique insights into ion channel structure and function. Moreover, venom-derived peptides are emerging as promising candidates for drug development, opening new avenues in pharmaceutical research. While traditional patch clamp techniques have been essential in this field, recent technological advancements have revolutionized toxin research. Automated patch clamp systems and parallel lipid bilayer recordings have dramatically improved our ability to study toxin effects on ion channels. These tools enable high-throughput screening and provide detailed mechanistic insights, accelerating the pace of discovery. At Nanion, we're proud that our instruments have contributed to numerous important discoveries in toxin research. Our technologies have been instrumental in studying a wide range of toxins, including marine, spider, scorpion, ant, bee, wasp toxins, and many more. If you're interested in how automated technologies can accelerate your toxin research, discover our recent flyer here: https://ow.ly/7mbW50UfIja or explore our dedicated webpage on toxin research and ion channels: https://ow.ly/iPoe50UfIjb #toxins #ionchannels #drugdiscovery #electrophysiology #apc

#Peptides and #DrugDiscovery – Part 4 As discussed in our previous post, advances in molecular biology led to significant breakthroughs in peptide drug discovery with the first approved peptide drugs. However, enhancing efficacy and identifying optimal peptide drugs remained challenging. Enter the 1990s-2000s, where advancements in peptide engineering made a significant impact. Stabilization techniques, such as cyclization and the incorporation of non-natural amino acids, were developed to enhance the therapeutic properties of peptides. Additionally, combinatorial chemistry and high-throughput screening technologies enabled the rapid identification and optimization of peptide candidates. These innovations paved the way for more effective and stable peptide therapeutics, marking another crucial stage in the journey of peptide drug discovery. What happened next? Stay tuned for our next post! Read our previous post here > https://lnkd.in/dkBPsVft #pharma #drugdevelopment

✨✨ Welcome to read the latest research "Molecular Hybridization as a Strategy for Developing #Artemisinin-Derived #Anticancer Candidates" by Dr. Maria Luisa Navacchia et al. 🔗 Paper link: https://lnkd.in/gd6yT27e Artemisinin, a natural product extracted from /Artemisa annua/ and approved as antimalarial drug, has also been explored as a potential anticancer drug. Indeed, drug repurposing is a relevant and increasingly pursued approach in the pharmaceutical sector. However, the therapeutic use of artemisinin is limited due to its poor stability and bioavailability. Molecular hybridization resulting from a covalent combination of artemisinin with one or more active pharmacophores has emerged as a promising approach to overcome several issues. The variety of hybridization partners lets improving artemisinin bioactivity by tuning the ability of hybrids to interact with various molecule targets involved in multiple biological pathways. The review highlights the current scenario of artemisinin-derived hybrids with potential anticancer activity with the aim to facilitate further rational design of more effective candidates.

Can we predict good %F for bRo5s? Beyond Rule of Five and PROTACs in Modern Drug Discovery: Polarity Reducers, Chameleonicity, and the Evolving Physicochemical Landscape, https://lnkd.in/eRQrrZsW by Edward Price et al. This article describes a high throughput experimental measurement of a new parameter, "chameleonicity" derived from an SFC Rt value to give an "experimental measure of exposed polarity" (EPSA) value. The ratio of EPSA/TPSA called ETR revealed that for bRo5s, an ETR value of <0.8 was good and <0.6 was better at predicting intestinal fraction absorbed (fa or faFg) >0.3. The study included ca. 10,000 AbbVie Ro5, bRo5 compounds, the latter including PROTAC compounds, as well as 29 bRo5 approved drugs. To predict for acceptible faFg, consideration of physicochemical property descriptors MW and lipophilicity (cLogP) graphed against faFg showed trends for acceptable values that differ when considering Ro5s, bRo5s, and PROTACs. Notably to achieve faFg>0.3, bRo5s do not tolerate MW>700 and cLogP>5 while PROTACs do achieve faFg>0.3 at MW>700 as long as cLogP>5 (Figure 4). This resulted in the prediction of "sweet spots" which connect acceptable faFg with MW and cLogP (Table 2, not included). Chameleonicity describes 3D folding effects of bRo5s in response to the polarity of their environment. Some molecules form extended linear conformations in water (think blood plasma) and then more compact conformations stabilized by intramolecular hydrogen bonds (IMHB) in nonpolar environments, (think lipids and membranes). To study chameleonicity, EPSA is determined chromatographically using a SFC method (see Goetz ref. 31) which due to its nonpolar eluent (CO2/MeOH) encourages IMHBs. EPSA values relate to Rt values from a standard curve: EPSA = a * Rt + b. With this, the authors introduce a handy new descriptor called ETR which is EPSA/TPSA (E/T ratio). This value can be used to describe dynamic molecular folding properties (chameleonicity). Evaluation of their large set of compounds led to some interesting trends. ETR = 1 indicates less polar, rigid rO5-like molecules. ETR<1 indicate chameleonicity via IMHBs with reduced polarity in non-polar media. PROTACs often have ETR<1. Sweet spots were uncovered. Compounds having TPSA>140 and ETR<0.8 often have acceptable faFg. Polar compounds (TPSA>180) with ETR<0.6 also can have good absorption. This suggests that increased polarity combined with increased flexibility can result in acceptable absorption. Again, the flexibility component indicates the capacity to assume a compact shape in a nonpolar environment. Polar compounds that are macrocycles often have low ETRs since they are already in a compact shape (see their Figure 9 with known bRo5 drugs, not included here). In general for bRo5s, lower ETR values (i.e. <0.6) portend better potential faFg (Figure 7). Further application of this ETR value relationship to faFg from other companies is expected to test its validity.

🧬 The free-state behavior of compounds in solution can have significant impact on the entire drug discovery process since it is one of the main sources of artifacts in assays. ✔ At NMX, we harness the versatility of NMR to evaluate solubility and aggregation of your molecules. ✔ We are a leader in the study and characterization of free-state behavior using biophysics. 👉 Want to learn more? Contact us to become a CRP (Contract Research Partner) with us and see how we can surpass your expectations of a traditional CRO. Email: nmx@nmxresearch.com now. More information about our services here: https://lnkd.in/g4FN_5bd #CRP #PRC #partenaire #recherche #contractuelle #contract #research #partner #ORC #CRO #biopharma #biophysics #pharma #pharmaceutical #drugdiscovery #medicament #innovation #specialization #FBDD

🎉 Publication Announcement: New Review Article We are pleased to announce the publication of another review article, titled "Peptide–oligonucleotide conjugation chemistry and therapeutic applications" authored by Anna Malinowska, Harley Huynh and Sritama Bose, PhD, in Current Issues in Molecular Biology, published by MDPI. The article looks into using peptide–oligonucleotide conjugates (POC) to overcome the delivery challenges associated with oligonucleotide-based therapeutics, such as poor tissue uptake and limited bioavailability. It provides a comprehensive overview of the strategies used to synthesise these conjugates, highlights commonly used peptides, and discusses the advantages and limitations of these methods for improving the therapeutic potential of oligonucleotides. You can now download the article from our website: https://lnkd.in/gW5eGtcD 🚀 Stay tuned for more updates from NATA as we continue advancing research in nucleic acid therapies! #Science #Research #Chemistry #Biology #Oligonucleotides #Pharma #Pharmaceutical #Therapeutics #DrugDiscovery #Biotech #Biotechnology #AdvancedTherapies #Healthcare #Impact #Innovation #Biochem #HealthcareInnovation #Publication

🔊 Upcoming webinar series - The Impact of Colloids and Nanoparticles on Intestinal Drug Absorption. Join us as we welcome Kiyohiko (Kiyo) Sugano, Ph.D., Professor at Ritsumeikan University, Japan who will give an overview of the particle drifting effect. The particle drifting effect (PDE) has attracted much attention as a mechanism to enhance oral drug absorption. This presentation will discuss the basic idea of PDE and clinical, in vivo, and in vitro data that suggest PDE. In most cases of poorly soluble drugs, oral absorption becomes the solubility-unstirred water layer (UWL) permeability limited (SL-U) (not dissolution-rate limited). However, when the dose strength is increased and/or particle size is reduced, the amount of oral drug absorption often increases above the maximum absorbable dose in preclinical in vivo studies and clinical studies. Because the saturated (equilibrium) solubility is not affected by the dose strength and particle size (unless < 100 nm), the UWL permeation is increased in these cases. When drug particles drift into the UWL, the flux across the UWL will increase. Join us to learn more and secure your spot by registering today! https://lnkd.in/e6XVcp5C #particlesize #drugabsorption #invivo #invitro #nanoparticles #particledrift #Pion #webinar

𝐈𝐧𝐭𝐚𝐯𝐢𝐬 𝐑𝐞𝐬𝐞𝐚𝐫𝐜𝐡 𝐑𝐨𝐮𝐧𝐝𝐮𝐩 "𝐂𝐲𝐜𝐥𝐢𝐜 𝐏𝐞𝐩𝐭𝐢𝐝𝐞𝐬 𝐟𝐨𝐫 𝐃𝐫𝐮𝐠 𝐃𝐞𝐯𝐞𝐥𝐨𝐩𝐦𝐞𝐧𝐭" The paper reviews the development and application of cyclic peptides as therapeutics. It discusses their unique properties, including high binding affinity, specificity, proteolytic stability, and improved membrane permeability, which contribute to their effectiveness as drugs. The paper also highlights technological advancements in the synthesis and screening of cyclic peptide libraries, which have expanded development opportunities beyond naturally derived molecules. Current challenges and opportunities, particularly in targeting intracellular proteins and enhancing oral bioavailability, are also explored. 𝐖𝐡𝐚𝐭 𝐚𝐫𝐞 𝐭𝐡𝐞 𝐤𝐞𝐲 𝐩𝐫𝐨𝐩𝐞𝐫𝐭𝐢𝐞𝐬 𝐨𝐟 𝐜𝐲𝐜𝐥𝐢𝐜 𝐩𝐞𝐩𝐭𝐢𝐝𝐞𝐬 𝐭𝐡𝐚𝐭 𝐦𝐚𝐤𝐞 𝐭𝐡𝐞𝐦 𝐬𝐮𝐢𝐭𝐚𝐛𝐥𝐞 𝐟𝐨𝐫 𝐝𝐫𝐮𝐠 𝐝𝐞𝐯𝐞𝐥𝐨𝐩𝐦𝐞𝐧𝐭? Cyclic peptides have high binding affinity and specificity, proteolytic stability, and in some cases, improved membrane permeability. These properties arise from their cyclic structure and peptidic composition, making them more effective than their linear analogs in drug development. Paper reference: Ji, X., Nielsen, A. L., & Heinis, C. (2024). Cyclic peptides for drug development. Angewandte Chemie International Edition, 63(3), e202308251. #IntavisResearchRoundup #CyclicPeptides #DrugDevelopment

I’m excited to announce a new publication from our collaborative project with Dr. Xuehua Zhang’s group, featured in ACS Applied Materials & Interfaces! This study focuses on the rapid detection of uremic toxins using Surface-Enhanced Raman Spectroscopy (SERS), addressing critical health challenges like oxidative stress, neurotoxicity, and chronic kidney disease progression. Key contributions of the study include: ⭐ Innovative 3D-printed microchamber: Developed by Dr. Zhang’s group to integrate plasmonic metal nanoparticles for in-flow SERS detection, achieving ultralow detection limits for biological toxins and pharmaceutical drugs. ⭐ Real-time, quantitative monitoring: Enables highly reproducible results with liquid volumes under 100 μL, making it ideal for point-of-care diagnostics. ⭐ Cost-effective synthesis approach: Implements an in situ method for silver nanoparticles, avoiding the need for expensive nanofabrication techniques. I’m grateful to have been part of this collaborative effort. Check out the full abstract below, and stay tuned for future developments from this exciting project! If you’re interested in discussing applications, feel free to reach out. https://lnkd.in/gGZTYzie