Journal of Medicinal Chemistry Collection: Drug Discovery in Italy

Abstract

We are pleased to introduce a Collection on “Drug Discovery in Italy” on behalf of the Journal of Medicinal Chemistry. Italy has a long tradition of excellence in drug discovery, with several drugs brought to the market. (1) Today, this tradition continues and the pharmaceutical sector is still one of the main drivers of the country’s economy. However, the sector is predominantly active in the production of active pharmaceutical ingredients (APIs), with only a few companies and highly specialized Contract Research Organizations (CROs) engaged in R&D. The main dissemination efforts are therefore made by academic medicinal chemists, who try their best, despite a wavering support from the Italian Ministry of Universities and Research (MUR). The Medicinal Chemistry Division of the Italian Chemical Society (781 members in 2024) plays an active role in promoting collaboration between all the drug discovery stakeholders in Italy, and established a permanent roundtable in September 2023. (2) The current situation is mirrored in the 208 manuscripts with corresponding authors affiliated with an Italian institution that were accepted for publication between January 2020 and August 2024 in the Journal of Medicinal Chemistry. An analysis based on institution type revealed that the majority (85%) of the publications feature corresponding authors working in academia, followed by contributions (9%) submitted by researchers working in national research centers or public research institutes managed by private foundations (e.g., the Italian Institute of Technology), and a minority (6%) of scientists working in industry. Interestingly, the majority (60%) of the publications from industry were contributed by researchers from Chiesi Farmaceutici S.p.A., whereas the other contributions were authored by researchers at Dompé Farmaceutici S.p.A. and Molecular Horizon srl, or at a Swiss multinational company (Novartis AG) or a German CRO (Aptuit srl, an Evotec company) based in Italy. To note, both Chiesi and Dompé belong to the so-called “Fab13”, (3) companies characterized by family control and a mission to keep a large part of their research and production in Italy, as well as their headquarters. Pleasingly, the publications covered a wide geographical distribution from Northern to Southern Italy, with 15 out of 20 Italian regions represented in the published research (Figure 1). The published work was distributed as follows: 40% of the publications featured corresponding authors affiliated with institutions in Northern Italy, followed by 36% and 24% of publications with corresponding authors working at institutions in Central and Southern Italy, respectively. These statistics are roughly in line with the demographic distribution within the Italian territory, whereby 46% of the population lives in Northern regions. To counteract depopulation and ensure a more homogeneous distribution of the funding, the National Recovery and Resilience Plan in 2021 (4) allocated 40% of the funds to PIs working in institutions in Southern Italy, with the aim of turning this region into a hub of excellence for research and innovation. Figure 1. Italian regions represented in this Collection. The blue shade reflects the number of publications featuring corresponding authors affiliated to an institution in the region. Gray regions represent areas with no contribution published in the considered time frame. Top right insets: publication type and corresponding author gender statistics of contributions published from January 2020 to August 2024. In terms of gender balance, 42% of the corresponding authors were female and 58% male. We also analyzed the seniority of the corresponding authors and observed that 24% of the publications featured at least one early-career researcher in a fixed-term academic contract as either the sole or co-corresponding author. Although this percentage is encouraging, most of the contributions can be ascribed to a few research groups. Nonetheless, we hope that these statistics will raise awareness of the importance of promoting the independence of early-stage researchers and encourage, in particular, early-career women to submit their best findings to the Journal of Medicinal Chemistry, the “Most Trusted, Most Cited, Most Read” in our field. For this collection, we have selected 47 representative documents, including 35 Articles, 10 Perspectives, one Editorial, and one Drug Annotation. We tried our best to keep a balance between research submitted by corresponding authors from all institution types, age, and gender groups as well as all geographical areas. Selection criteria encompass the total number of views and citations the publications received in relation to the date of their first online appearance. Articles published in 2020 were included if they attracted more than 40 citations, whereas the most recent publications were included if they attracted a considerable number of views (i.e., more than 2000 views for articles published in 2024). As far as Perspectives are concerned, we included the top five most cited and a selection of Perspectives attracting a high number of views, weighted for the number of citations, proportionally to the elapsed time since their first online appearance. A visual recap of the most investigated drug targets and compound types reported in the selected documents is pictured in Figure 2. Figure 2. Word cloud showcasing the most investigated drug targets, compound types, pathologies, and techniques reported on the contributions published from January 2020 to August 2024 selected for this Collection. The medicinal chemistry questions most investigated in the Articles and the Drug Annotation include the design and development of proteolysis targeting chimeras (PROTACs), followed by dual and multi-target-directed ligands. The development of novel anticancer small molecules and peptide analogues is the most popular line of research, whereas therapeutic areas such as, among others, epilepsy and Alzheimer’s disease were sought as well. The selected Editorial focuses on the challenges associated with the development of radiopharmaceutical compounds for imaging purposes. Most of the novel compounds described in the publications are either enzyme and protein–protein interface inhibitors, with a minority of small molecules acting as channel blockers/activators and synthetic glycolipids acting as receptor agonists. With respect to PROTACs, compound solubility and metabolism are among the most finely tuned and thoroughly investigated properties, along with chemical chameleonicity. As far as the other classes of compounds are concerned, selectivity, off-target activity, and toxicity screening, as well as the pharmacokinetics profile of at least the most promising candidate, are reported, in compliance with the Journal of Medicinal Chemistry guidelines and Editors’ recommendations. (5) Other aspects worth mentioning are the design and development of both beyond rule of five (bRo5) compounds, on one hand, and fragments of both standard and ultralow molecular weight, on the other hand, and the increasing interest in using NMR as a screening platform. In 23% of the selected Articles, the in silico-driven design was explicitly acknowledged, whereas the majority (66%) of publications exploited both ligand- and structure-based methods to predict compound properties or rationalize the observed data. Interestingly, 17% of the selected Articles supported their findings with X-ray structures of the investigated target in complex with at least one newly synthesized analogue. Among the Perspectives, fighting antibiotic resistance and SARS-CoV-2 infections are the topics that collectively attracted the highest number of citations, followed by using innovative techniques in synthetic chemistry to reduce and speed up the number of design–make–test cycles needed in drug discovery, along with the design of chimeric ligands for chemical biology applications. Other topics attracting readers’ interest are drug nomenclature, essential medicines, privileged scaffolds, and synthetic lethality in cancer. Overall, the variety and timeliness of the medicinal chemistry research programs conducted in Italy, as reflected in the selected contributions, reveal a dynamic and thriving research environment encompassing institutions across the country from North to South. Pleasingly, the medicinal chemistry research pictured in this Collection seems to have proceeded full-steam-ahead, despite the lack of a systematic and sustained funding program from our government. We hope this excellent result will contribute to boost a vision change that it is hoped will grant both senior and junior generations of medicinal chemists access to more regular and structured funding mechanisms, which will in turn further enable them to conduct high-quality drug discovery projects that will be published in the Journal of Medicinal Chemistry. This article references 5 other publications. This article has not yet been cited by other publications.