Maria Serena Fabbrini ^1,2* Riccardo Vago ^3,4*

• ¹ Independent researcher, 20900 Monza, Italy, Italy
• ² B&F bioConsulting, Monza, Italy
• ³ Urological Research Institute, San Raffaele Scientific Institute, Milan, Lombardy, Italy
• ⁴ Vita-Salute San Raffaele University, Milan, Lombardy, Italy

double-blind clinical studies should become an integral part of the development of small single therapeutic compounds in future TCM (Huang et al., 2024). We aimed giving here a brief overview on nNovel potential therapeutic treatments, mentioning the artificial intelligence-assisted, multidisciplinary approaches that will need to integrate the wide multi(omics) data we are generating, to develop a precision medicine able to exploit the most advanced molecular/chemical tools. In this context, the future of pharmacology leading to personalized medicine goes also through repositioning approved drugs' use, to speed-up the whole process while drastically reducing costs. Tools such as "omics" and machine deep learning technology will drive our better understanding on drug mechanism(s) of action, thus facilitating the repurposing process. Acetylsalicylic acid, firstly commercialized against pain, as antipyretic and anti-inflammatory drug, then observed to be active in preventing cardiovascular diseases like myocardial infarctions or stroke, has a long versatile future ahead: lately aspirin has been proposed to play a role in reducing cancer incidence and metastatic spread (Montinari et al., 2019;Sikavi et al., 2024). Being an irreversible inhibitor of cyclooxygenase, aspirin blocks the prostaglandins (PG) and thromboxane A2 (TXA2) synthesis, interfering with multiple pathways leading to disease onset. As reported by (Patrignani et al., 2024) aspirin counteracts PGE2 and TXA2 biosynthesis in platelets and myofibroblasts both being enhancers of proliferative and migratory capabilities in the tumor microenvironment. Clinical trials follow-up is assessing the impact of low-dose aspirin in hereditary colon cancer CAPP3 known as Lynch syndrome (https://www.capp3.org/). Clopidogrel, one of the ADP receptor antagonist family, normally recommended for the reduction of atherosclerotic events, including myocardial infarction and ischemic stroke, which forms a disulfide bridge with extracellular cysteines of the P2Y12 receptor, could counteract with other P2Y12 inhibitors Adenoma in patients with sporadic cancer. Drug repurposing will greatly impact new uses of "old" or investigational drugs that may result from accidental discoveries of off-targets such as with thalidomide, later repurposed to treat leprosy and multiple myeloma. Hundreds of drugs have moved into clinical trials during COVID-19 and four drugs received FDA emergency use authorization, with an additional 15 drugs being recommended for off-label use (Patrignani et al., 2024). SARS-CoV2 treatment is the subject of computer-aided drug design (CADD), used in modelling drug-target interactions for inhibiting the main endo-protease M pro (Dai et al., 2023), which is a potential powerful explorative predictive tool, despite safety, preclinical data, pharmacodynamics, and clinical studies need to be conducted to identify the lead drug candidate. Another in-silico approaches was used for designing and then synthesizing tyrosinase inhibitors which underwent high-resolution mass spectroscopy and Fourier infrared analyses (Ahmad et al., 2024). The purified compounds were refluxed with aldehydes and ketones in a step-by-step innovative and costeffective process to identify a lead compound. Mammalian tyrosinase is a single transmembranespanning polypeptide and in humans, tyrosinase is sorted to melanosomes where it is involved in the melanin synthesis and is a biomarker for several skin diseases, as an anti-melanogenesis target. French et al. (French et al., 2023) developed a live-cell assay, termed "ClickArr", that simultaneously reports recruitment of both β-arrestin 1 and 2 isoforms, as they compete for interaction with delta opioid receptor (δOR). This drug screening platform provides researchers tools to design drugs that may optimize analgesic efficacy while reducing tolerance development. Beta-arrestin-1 and 2 indeed, are multifunctional intracellular isoforms that modulate cell signaling by regulating desensitization, internalization, and re-sensitization of G protein-coupled receptors (GPCRs), including δORs. Their interactions with δORs are critical to understand receptors' main function in a variety of pathological processes, such as migraine, neuropathic pain, and alcohol abuse disorder. Different δOR agonists preferentially recruit specific β-arrestin isoforms and this specific recruitment plays a crucial role in determining the functional outcomes of receptor activation to trigger subsequent signaling pathways ha formattato: Apice ((Pradhan et al., 2016). The nuanced roles of β-arrestins in δOR signaling gives the opportunity for developing "biased" agonists which may selectively activate beneficial signaling pathways while minimizing adverse effects. Furthermore, this modelling could be developed for other GPCRs beyond the δOR, extending it to a diverse array of prospective drug targets. Finally, the article by (Ahmad et al., 2024) made use of in-silico approaches for designing and then synthesizing tyrosinase inhibitors which underwent high-resolution mass spectroscopy and Fourier infrared analyses. The purified compounds were refluxed with aldehydes and ketones in a step-by-step innovative and cost-effective process to identify a lead compound. Mammalian tyrosinase is a single transmembrane-spanning polypeptide and in humans, tyrosinase is sorted to melanosomes where it is involved in the melanin synthesis and is a biomarker for several skin diseases, as an anti-melanogenesis target. The next ten years of experimental pharmacology will be marked by significant challenges that require innovative solutions to be overcome. Integration of new technologies and collaborative efforts across disciplines can offers promising directions for improving the drug discovery process.