Herbal medicine plays a significant role in treatment in various traditional medical systems worldwide [1-5]. Among such traditional medicine systems, Ayurveda has been a cornerstone of health care for a significant portion of the Indian population for centuries [6]. Despite its long-standing use, the scientific community’s acceptance of Ayurveda as an evidence-based health system remains tempered due to the lack of evidence-based data regarding the mode of action of Ayurvedic formulations.

Over the last 3 decades, substantial effort has been made to assess the effectiveness of Ayurvedic formulations. Traditional pharmacology tools, including in vivo and in vitro models, have been the most common means used for evaluating the preclinical efficacy of these formulations [7]. However, a persistent issue has been the lack of a detailed explanation regarding how these compounds work within the framework of modern science. This poses a challenge in establishing a robust scientific evidence base for Ayurveda. Thus, further efforts are needed to address the critical question of how Ayurvedic formulations work to justify their widespread use in health care.

There has been a notable shift toward the development and application of computational and in silico methods in pharmacological research [8]. These techniques have increasingly been used for formulating and testing various hypotheses related to a drug’s mode of action. In particular, in silico screening has emerged as a powerful tool for predicting a drug’s potential mechanism of action and its impact on specific target proteins of the human body. Thus, in silico studies that can identify lead compounds in polyherbal formulations (PHFs) and subsequently predict the molecular mechanism of action hold immense promise in the domain of Ayurvedic drug development.

To date, in silico approaches in understanding traditional medicine have mainly focused on single herbs. Although individual herbs contain hundreds of diverse phytochemicals, when combined to form PHFs, some of the original phytochemicals may be lost. In addition, the manufacturing process of a PHF may introduce new phytochemicals, resulting in a complex and dynamic mixture of metabolites [9]. This complexity necessitates a distinct approach in understanding the pharmacological properties of PHFs.

Although established methods are available for conducting in silico studies on individual herbs, little is known about strategies for in silico studies on PHFs. Therefore, the aim of this scoping review is to identify and chart the diverse in silico approaches that are currently being explored to understand the mechanism of action of PHFs, which can further help to identify the existing knowledge gaps in this area to target efforts for future research directions.

A preliminary search of MEDLINE, Cochrane Database of Systematic Reviews, and Joanna Briggs Institute (JBI) Evidence Synthesis database yielded no ongoing or completed scoping reviews on this specific topic. Apart from Ayurveda, other traditional medicine systems also depend on PHFs for the management of diseases. Considering the primary focus on PHFs, our search scope will extend to other traditional systems of medicine, ensuring a comprehensive understanding of the potential applications of in silico techniques in studying PHFs across different medical systems.

An initial search was performed on the PubMed database using the keywords and strategy outlined in Table 1. The initial search yielded 3865 studies. After applying filters such as full-text availability, articles published in English, and those published between January 2021 and December 2023, 875 studies were obtained. As the study progressed, the search strategy was changed. The Boolean term “NOT” was removed and additional keywords were included.

The findings of this scoping review are expected to address the specific review questions and identify knowledge gaps related to the methods used for the phytochemical identification of PHFs, determine the criteria for target selection, and propose evidence-backed methods for conducting in silico studies on PHFs.

This scoping review will be the first of its kind in providing a comprehensive understanding of the potential applications of in silico techniques in studying PHFs across different traditional medicine systems. The findings will also be interpreted in a manner that can facilitate evaluating the effectiveness of these methods for gaining a better understanding of the mechanism of drug action.

In silico approaches have proven to be significant in identifying novel drug candidates and repurposing existing drugs [12,18,19]. These studies have also been instrumental in shedding light on the likely mechanisms of action of single herbal drugs [20]. However, the in silico strategies used to study PHFs are not well understood. Several methods appear to be used to conduct in silico studies on PHFs [21,22]. This scoping review can thus help to identify the most effective in silico methods in this context and can further help to guide the design of future in silico studies on various types of PHFs used in traditional medicine.

The scoping review is limited by its reliance on in silico studies, which can offer valuable preliminary insights but may not fully capture the complex interactions and bioavailability of compounds within PHFs when administered in vivo. Additionally, this review might encounter limitations due to the variability of methodologies and the quality of reporting across in silico studies, potentially affecting the consistency and comparability of findings related to the efficacy and safety of PHFs.

The future scope and perspectives of this field that can be informed by this scoping review are depicted in Figure 1. The results of in silico studies can be further validated through preclinical and clinical studies. Multiomics strategies such as genomics and metabolomics can also be applied. The review seeks to provide an overview of the progress made in employing in silico techniques to decipher the mechanisms underlying the efficacy of PHFs, thereby contributing to our understanding of this critical aspect of traditional medicine.