1. EMERGING PARADIGMS IN NATURAL PRODUCT DISCOVERY
The landscape of natural product drug discovery is progressively shifting from laboratory-based isolation from crude drugs to the incorporation of integrative omics and advanced analytics to scrutinize the wider range of chemical diversity. The fast development of omics, analytical instrumentation, and AI technology significantly contributed to regaining the declining interest of pharmaceutical companies regarding the acquisition of new bioactives, which was a very tedious and time-consuming process previously. Moreover, the discovery of known compounds from the complex natural mixtures can be avoided via advanced analytical approaches like tandem mass spectrometry-based molecular networking [3]. Furthermore, the integrative genome-to-metabolome approach incorporates high-throughput characterization of bioactive metabolites in natural products using sophisticated spectrometric techniques. Overall, the metabolomics profiling facilitates revealing the bioactive metabolites more efficiently [4]. ML tools also guide the efficient natural products discovery due to the availability of huge data on natural product biosynthesis that became possible because of recent advancements in bioinformatics and genome mining strategies. Various kinds of biological activities, like antimicrobial, anti-cancer, and anti-inflammation activities, and target prediction, can be predicted via ML tools, as they offer an exclusive opportunity to link molecular structures of natural products with bioactivity [5]. Synthetic biology, heterologous expression, and metabolic engineering methodologies are helpful in the bio-production of worthwhile medicinal natural products. Synthetic biology helps connect predictions with real production. Transferring plant pathways into microbes or other host plants allows researchers to test whether a predicted pathway is correct, make large quantities of rare metabolites, and develop new analogs that are hard to obtain from the original plant. Such strategies reduce the need to harvest slow-growing or scarce species and make medicinal chemistry work easier to perform on natural scaffolds. Recent studies have shown steady progress in rebuilding pathways for complex terpenoids and alkaloids, although challenges remain in predicting enzyme functions and controlling pathway regulation [6,7].
2. TRANSLATIONAL CHALLENGES IN DEVELOPING PLANT-BASED NATURAL PRODUCTS INTO DRUGS
Apart from promising biological activities from plant-derived natural products, converting them into clinically beneficial drug products remains a herculean task. Several obstacles, i.e., regulatory hurdles, access to biological sources, isolation and screening challenges, and low yield, restrain their translational potential; therefore, their full therapeutic potential is still underexplored. All these hindrances have shifted the focus of the pharmaceutical sector away from natural sources and back toward synthetic compound libraries of synthetic compounds [8]. Furthermore, the effectiveness and therapeutic response of phytoconstituents can be compromised due to biopharmaceutical challenges such as their reduced solubility and bioavailability problems [9]. Even when a plant compound exhibits potent in vitro bioactivity, its drug development may be limited by poor absorption, rapid metabolism, low solubility, or instability in vivo. Many phytochemicals, especially polyphenols, flavonoids, or other secondary metabolites, suffer from low oral bioavailability or rapid clearance, limiting their translational potential [10] .
Shortage of biological sources and environmental factors affects the availability of bioactives found in nature that directly affect the scalability and commercialization of natural product drug development. Besides that, the cultivation techniques and geographic location make it challenging to ensure the consistency and standardization of natural products. The naturally occurring compounds may face patentability limitations in their unmodified form; however, structural derivatives, novel formulations, new therapeutic indications, and manufacturing processes remain patentable. It can also be difficult to connect traditional knowledge with modern scientific standards, since this process raises cultural, ethical, and practical challenges. Consequently, regulatory hurdles are generated for natural-product-derived drug development [11] .
2.1. Future opportunities
As the natural-product field develops, a number of strategic shifts are emerging that could help to bridge the gap between drug discovery and therapeutic development, particularly for plant-derived compounds. The sophisticated extensions of AI, like ML and deep learning, are already exploring how we employ genomes and biosynthetic pathways for further validation. Recent work underscores how AI-driven analysis of omics and metabolic data can accelerate pathway identification and optimization, minimizing the need for laborious experiments. AI incorporation in pathway discovery and mining facilitates the rapid development of previously unexplored biological substances [12] .
Hybrid workflows can integrate natural product discovery, computational design, and biosynthetic engineering for better efficiency in comparison to their individual integration. Utilizing computational chemistry and AI to predict modifications or analogs, then producing them via engineered biosynthetic pathways, can yield drug-like derivatives of plant compounds more suited to development (Fig. 1). Rigorous standards for data reporting, extraction methods, compound characterization, and bioactivity assays must be adopted by the community if natural-product drug discovery is to scale. As noted recently, reproducibility suffers without standardization and proper data annotation, while AI-driven approaches will be similarly hindered by inconsistent or poor-quality datasets [13]. Investment in protocols for reproducible extraction, documentation of source materials, such as plant origin and growth conditions, and metadata standards across labs will strengthen reliability and regulatory readiness. The partnership between academia, biotech, and the pharmaceutical sectors is essential for strengthening the cross-sector collaboration for efficient natural product drug development. By developing collaboration among synthetic biology, medicinal chemistry, phytochemistry, and clinical development, the translational success for natural product development can be accelerated.
 | Figure 1. Integration of AI, combinatorial chemistry, and biosynthetic engineering in enhancing natural product drug development. [Click here to view] |
The future of plant-based natural-product drug discovery lies in exploring a hybrid, technology-enabled, and collaborative paradigm. By integrating AI with traditional wet-lab work, building shared data infrastructure, committing to rigorous standardization, and fostering cross-sector partnerships, the field can move beyond isolated discoveries toward sustainable pipelines and ultimately deliver novel therapies for unmet medical needs.
3. CONFLICTS OF INTEREST
The authors report no financial or any other conflicts of interest in this work.
4. PUBLISHER’S NOTE
All claims expressed in this article are solely those of the authors and do not necessarily represent those of the publisher, the editors and the reviewers. This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.
5. USE OF ARTIFICIAL INTELLIGENCE (AI)-ASSISTED TECHNOLOGY
The authors declare that they have not used artificial intelligence (AI)-tools for writing and editing of the manuscript, and no images were manipulated using AI.
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