Natural Products Driven Medicinal Chemistry

Abstract

RecommendationsN atural products (NPs) are organic compounds produced by living organisms, including plants, microorganisms, animals, and marine species.NPs have a rich history of contributing to new therapeutic medicines.NPs have evolved structurally to fulfill specific biological functions and typically exhibit a broader chemical diversity, characterized by a high number of sp 3 carbon atoms and chiral centers. 1 In this Virtual Special Issue (VSI), we aim to showcase drug discovery efforts based on NPs, highlighting the isolation of new NPs with bioactive properties, as well as lead optimization initiatives driven by NPs.This VSI is a cross-journal thematic collection of articles by six journals of the American Chemical Society, including the Journal of Medicinal Chemistry, ACS Medicinal Chemistry Letters, ACS Bio & Med Chem Au, Journal of Natural Products, ACS Chemical Neuroscience, and ACS Chemical Biology.The papers included in this VSI encompass research articles, letters, and perspectives published in their respective host journals.We welcomed a wide range of submissions of all manuscript types related to various aspects of NPs.Several articles in this issue comprise the integration of NPs with synthetic pharmacophores to enhance pharmacological effects or improve absorption, distribution, metabolism, and excretion (ADME) profiles.This VSI also includes articles focused on the isolation of new NPs and the investigation of their biological potential.Additionally, it highlights the identification of hits or starting points for medicinal chemistry through virtual screening of NP-based molecular libraries, along with experimental validation of these hits.The contribution of NPs in drug discovery has been periodically assessed by Newman and Cragg. 2 The analysis has shown that infection, oncology, and neurodegenerative diseases are largely dependent on NP-based scaffolds.This VSI includes two perspectives that critically analyze the contribution of NPs in drugs and clinical candidates.Paul D. Leeson conducted a study of clinical phase compounds and approved drugs, revealing that most target classes show a greater NP character in clinical compounds compared to their reference compounds.Notably, only 176 NP fragments were found in over 1,000 clinical compounds published since 2008, yet these fragments accounted for an average of 63% of the core scaffolds in clinical compounds.Another study by Domingo-Fernańdez and colleagues examined molecules in clinical trials and assessed the success rates from phase I to phase III.Their findings indicated that NPs demonstrated higher success rates throughout the drug development process.While 65% (3,085 out of 4,749) of compounds entering Phase I were synthetic, this figure dropped to 55.5% (1,863 out of 3,356) in Phase III.In contrast, the proportion of NPs rose from approximately 20% (940 out of 4,749) in Phase I to

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