The outbreak of coronavirus disease 2019 (COVID-19), triggered by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed unprecedented challenges to global health and economic stability for over three years. Amidst this crisis, traditional Chinese medicine (TCM) has emerged as a beacon of hope, offering promising avenues for mitigating the pandemic’s impact. Early intervention with TCM has been increasingly recognized for its potential to enhance recovery rates, reduce the duration and severity of illness, delay disease progression, and lower mortality rates among COVID-19 patients. This recognition is backed by a growing body of research, highlighting the importance of TCM in the contemporary medical landscape (Luo et al., 2020; Ren et al., 2020).
Despite the promising outcomes associated with TCM treatments, the scientific community continues to grapple with a significant challenge: the intricate nature of TCM makes it difficult to decipher the molecular mechanisms underlying the efficacy of its active ingredients. To bridge this gap, researchers employ a myriad of sophisticated techniques aimed at identifying and understanding the active components within TCM formulations.
These methodologies range from biological chromatography and capillary electrophoresis combined with high-performance liquid chromatography-tandem mass spectrometry to affinity ultrafiltration, equilibrium dialysis, surface plasmon resonance, three-dimensional cell bioreactors, and magnetic ligand fishing among others (Chen et al., 2021; Li et al., 2015; Wang et al., 2018; Zhu et al., 2022). However, these methods, despite their precision and efficiency, are often marred by complexity, time consumption, and a propensity for false positives due to nonspecific compound interactions, underscoring the need for more streamlined and reliable approaches (Montesano et al., 2016; Wang et al., 2017).
In this context, the advent of computer-based molecular docking and virtual screening technologies has revolutionized the field of drug discovery, including the exploration of TCM. These computational methods offer a cost-effective and time-efficient means of identifying potential active ingredients within TCM formulations by simulating their interactions with biological targets (Leman et al., 2020; Torres et al., 2019). Recognizing the immense potential of these technologies, our research endeavors to harness molecular docking to expedite the discovery of active TCM ingredients with antiviral properties against SARS-CoV-2.
Central to our approach is the targeting of 3-chymotrypsin-like protease (3CLpro), a key enzyme implicated in the replication of SARS-CoV-2, making it a critical target for antiviral interventions (V’Kovski et al., 2021). Our investigation focused on four TCM prescriptions known for their antiviral efficacy: Xuebijing injection, Tanreqing capsule, Lingmao formula, and Baqi Lingmao formula. Notably, Xuebijing injection has demonstrated remarkable effectiveness in treating COVID-19 by mitigating severe complications such as mechanical ventilation, septic shock, and cytokine storms, without adverse effects over a 14-day treatment period (Luo et al., 2021).
Similarly, the Tanreqing capsule has shown to expedite recovery in patients with mild to moderate COVID-19 by reducing the duration of nucleic acid and pharyngeal-fecal nucleic acid transfer (Zhang et al., 2021a). Furthermore, Lingmao Formula and Baqi Lingmao formula, traditionally used against chronic hepatitis B, possess anti-viral and anti-inflammatory properties that may be repurposed to combat COVID-19, considering the antiviral potential of nucleoside reverse transcriptase inhibitors (NRTIs) against SARS-CoV-2 (Karbasforooshan et al., 2022).
Our innovative strategy employs fluorescence resonance energy transfer (FRET) as an initial screening tool to identify promising single herbs from the selected TCM prescriptions, based on their inhibitory activities against 3CLpro. Subsequent analysis through the TCM systems pharmacology database and analysis platform (TCMSP) facilitated the identification of 19 ingredients with potential inhibitory effects on 3CLpro. Among these, robinetin, oleuropein, pentagalloylglucose, and methyl rosmarinate emerged as potent inhibitors, showcasing the efficacy of our method in pinpointing active ingredients capable of thwarting SARS-CoV-2 replication. Notably, methyl rosmarinate was identified as an allosteric inhibitor of 3CLpro, underscoring its potential as a therapeutic candidate against SARS-CoV-2 infection.
…….let’s break down the provided statement step by step:
Introduction to the Strategy: The strategy being discussed involves the utilization of a technique called Fluorescence Resonance Energy Transfer (FRET) as an initial step for screening potential herbal candidates. This screening process is aimed at identifying single herbs from Traditional Chinese Medicine (TCM) prescriptions that possess inhibitory activities against a specific target known as 3CLpro, which is an enzyme crucial for the replication of the SARS-CoV-2 virus. Fluorescence Resonance Energy Transfer (FRET): FRET is a physical phenomenon where energy is transferred between two fluorophores (molecules that emit light) when they are in close proximity. In this context, FRET is used as a tool to detect interactions between molecules, helping to identify compounds that interact with 3CLpro.Selection of Herbal Candidates: Through the FRET screening process, certain single herbs from Traditional Chinese Medicine formulations are identified as potentially having inhibitory effects on 3CLpro.
Utilization of TCMSP Database: Once potential candidates are identified, they undergo further analysis using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and analysis platform. This database provides information on the pharmacological properties and mechanisms of action of various compounds used in Traditional Chinese Medicine.
Identification of Active Ingredients: The analysis through TCMSP leads to the identification of 19 specific ingredients from the selected herbs that show potential inhibitory effects on 3CLpro. These ingredients are believed to have properties that could hinder the activity of the enzyme responsible for SARS-CoV-2 replication.
Identification of Potent Inhibitors: Among the 19 identified ingredients, four compounds – robinetin, oleuropein, pentagalloylglucose, and methyl rosmarinate – are highlighted as particularly potent inhibitors of 3CLpro. This suggests that these compounds have a strong capability to interfere with the enzyme’s activity, potentially hindering the replication of the SARS-CoV-2 virus.
Significance of Methyl Rosmarinate: Notably, methyl rosmarinate stands out as an allosteric inhibitor of 3CLpro. An allosteric inhibitor is a type of inhibitor that binds to a site on the enzyme other than the active site, thereby modulating its activity. This finding underscores the potential of methyl rosmarinate as a therapeutic candidate for combating SARS-CoV-2 infection by targeting 3CLpro through a mechanism different from traditional active site inhibitors.
In summary, this approach combines advanced screening techniques, computational analysis, and traditional knowledge of herbal medicine to identify promising compounds from Traditional Chinese Medicine that have the potential to inhibit 3CLpro, a key enzyme involved in SARS-CoV-2 replication. The identification of potent inhibitors, particularly methyl rosmarinate as an allosteric inhibitor, highlights the effectiveness of this strategy in discovering novel therapeutic candidates for combating COVID-19.
This study not only exemplifies the integration of traditional wisdom with modern scientific methodologies but also paves the way for the rapid discovery and development of novel antiviral agents derived from TCM. By elucidating the molecular mechanisms of TCM and harnessing the power of computational technologies, we edge closer to unveiling new horizons in the global fight against COVID-19, offering hope for more effective treatments in the face of ongoing and future pandemics.
reference link : https://www.sciencedirect.com/science/article/abs/pii/S0166354224000494
