Bentham Science Newsletter

Medicinal Chemistry Spotlight

News about Medicinal Chemistry Advances

Medicinal Chemistry Spotlight | Bentham Science

In this issue, we take a look at recent news in medicinal chemistry.

Harnessing Deep Learning to Supercharge Conotoxin-based Drug Discovery

Conotoxins are a family of small, highly potent peptides produced in the venom of predatory marine cone snails (Conus species). These disulfide-rich peptides evolved to target ion channels and receptors with remarkable affinity and subtype selectivity, making them valuable both as pharmacological tools and as lead compounds for drug development. Conotoxins have already yielded clinical therapies (e.g., ziconotide for chronic pain) and numerous research probes targeting nervous system signaling pathways.

A new Nature Communications study introduces CreoPep, an advanced deep learning platform designed to accelerate the creation and optimization of conotoxin-based peptides for specific biological targets. By combining masked language modeling with physics-based filtering and smart sampling techniques, CreoPep generates structurally diverse peptide variants that maintain essential pharmacological features. The source files are available here. Early validation shows that CreoPep can design peptides targeting key receptors such as nicotinic acetylcholine receptor subtypes with promising binding profiles. This research marks a significant step forward in rational peptide engineering, offering a scalable computational-experimental framework to expand conotoxin diversity and guide the discovery of next-generation peptide therapeutics for neurological, pain, and other receptor-mediated disorders.

Zasocitinib: A Next-Generation TYK2 Inhibitor Redefining Immune Therapy

Zasocitinib (TAK-279) is an investigational oral, allosteric inhibitor of Tyrosine Kinase 2 (TYK2) being developed to treat immune-mediated inflammatory diseases (IMIDs) such as psoriasis, psoriatic arthritis and inflammatory bowel disease. Unlike traditional JAK inhibitors that broadly target multiple Janus family kinases, zasocitinib binds selectively to the JH2 regulatory domain of TYK2, avoiding interference with JAK1, JAK2 or JAK3 — enzymes involved in many normal immune and physiological processes. This unique allosteric approach offers the potential for targeted suppression of key inflammatory pathways (e.g., IL-12, IL-23, type I interferons) while minimizing side effects linked to wider immune inhibition.

A major challenge in developing TYK2 inhibitors has been the high structural similarity between TYK2 and other JAK kinases, making selective targeting difficult without cross-reactivity. To overcome this, researchers used AI-assisted structure-based design and advanced computational modeling to screen and refine candidate molecules, ultimately optimizing selectivity, solubility and pharmacokinetics. Early leads were iteratively improved by eliminating off-target activity and enhancing metabolic stability, resulting in a potent compound suitable for once-daily oral dosing.

Preclinical and simulated pharmacology data show that a 30 mg once-daily dose of zasocitinib can maintain more than 90 % TYK2 inhibition over 24 hours without measurable activity against JAK1/2/3 — a profile superior to existing TYK2 inhibitors such as deucravacitinib in comparable models. Zasocitinib is currently advancing through late-stage clinical trials (Phase III in plaque psoriasis and Phase II/III in other IMIDs), where early results indicate strong efficacy and a favorable safety profile. If approved, it could offer a more targeted, potent and better tolerated oral therapy for patients with chronic inflammatory diseases.

Natural Compounds Betulinic Acid and Taraxerol Show Promise Against Asthma

A recent study explored the potential of two natural molecules, betulinic acid (BA) and taraxerol (T), in relieving asthma symptoms. Researchers tested these compounds in experimental models and also performed molecular docking studies to see how they interact with key asthma-related receptors.

Using Bacopa monnieri (Water hyssop) leaf extracts, the team compared BA and T against a standard asthma drug, budesonide, in guinea pigs. The molecular docking study revealed that BA and T strongly bind to LOX-5, an enzyme involved in producing leukotrienes, which play a major role in asthma inflammation.

In the animal experiments, BA and T delayed asthma-induced convulsions, reduced inflammatory markers like TNF-α, and increased anti-inflammatory IL-10. They also lowered oxidative stress, improving antioxidant enzyme activity (SOD, CAT, GSH) and reducing lipid peroxidation (MDA). Histological analysis confirmed less airway inflammation and remodeling in treated animals.

Overall, the study suggests that BA and T modulate inflammation, protect against oxidative lung damage, and reduce bronchial hyperresponsiveness. These findings point to the potential of these natural compounds as future alternatives or complements to current asthma therapies.

Advanced Glycation End Products and Autoimmune Skin Disorders in Type 1 Diabetes

Advanced Glycation End Products (AGEs) are molecules formed when sugars attach to proteins, lipids, or DNA without enzymes — a process that speeds up in Type 1 Diabetes (T1DM). AGEs bind to the RAGE receptor, triggering oxidative stress and inflammation through Reactive Oxygen Species (ROS). They can also modify normal proteins, creating neoantigens that the immune system mistakenly attacks, contributing to autoimmune skin diseases like vitiligo and bullous pemphigoid.

Current research suggests that AGEs worsen oxidative stress, deplete antioxidants, and damage skin cells. Hypoxia (low oxygen) further amplifies ROS, though emerging approaches like oxygen nanobubbles may help.

Therapies targeting AGEs, oxidative stress, and immune dysregulation show promise. AGE inhibitors (aminoguanidine, pyridoxamine) reduce harmful protein modifications, while antioxidants (vitamins C & E, polyphenols, selenium, N-acetylcysteine) neutralize ROS. Immune-based treatments, including Treg therapy, cytokine inhibitors, and RAGE antagonists, aim to restore tolerance and reduce inflammation. Combining these strategies could protect against skin autoimmunity in T1DM.