Assessing knowledge of herbal medicine course for dental students.

BACKGROUND: The aims of this article are to assess dental students' knowledge about herbal medicine usage and the potential benefits and side effects, and to conduct a short course about herbal medicine. METHODS: All fourth-year pre-doctoral students were invited to participate in a herbal medicine course as a test while the sixth-year students were the control group. A survey was tested for validity and reliability. It comprised of 16 multiple choice questions was given before the course and one month after the course. The sum score of knowledge for each participant was calcuated based on the ability to identify the use of herbs in dentistry with high-quality evidence (correct answer) or total answer for periodontal disease and caries. RESULTS: The response rate for completing the study was 112 fourth-year students (73.7%) and 64 sixth-year students (39.0%). More than half of the participants (52.5%) were unsure about the importance of herbal medicine in dentistry. However, the majority also stated that the most common herbs used in dentistry were clove (62.9%), followed by curcuma turmeric (54.7%) and meswak (43.0%). The fourth-year students displayed evidence of a higher overall knowledge score after the course in herbal medicine related to periodontal disease in total and correct answers (mean 4.48 ± 4.13, 3.73 ± 3.31, respectively) compared to before the course (mean 0.84 ± 1.23, 0.74 ± 1.16, respectively) (p-value < 0.001). The post-course periodontal disease total and correct answers were statistically significant between fourth- and sixth-year students. CONCLUSION: Herbal medicine has a potential positive impact on dentistry. However, these effects are not fully investigated and received full attention in academic institute. This short educational program related to medicinal herbs can improve the knowledge of dental students. This will help increase the awareness about the use and potential side effects of herbal medicine in the dental field.

Herbal Medicine Uses for Respiratory System Disorders and Possible Trends in New Herbal Medicinal Recipes during COVID-19 in Pasvalys District, Lithuania.

Despite some preliminary studies of the available herbal medicine preparations and their curative effects on COVID-19, experts still fear that unproper use of such homemade medicines could do more harm than good to people relying on unproven alternatives of questionable efficacy. The main purpose of this study was to evaluate the safety of herbal medicines used for respiratory system disorders in the Pasvalys district during the COVID-19 pandemic in Lithuania. An archival source was also studied, looking for possible recipes for the treatment and prevention of respiratory diseases in Lithuanian traditional medicine, emphasizing the safety guidelines. The survey was conducted using the deep interview method. The respondents mentioned 60 species of medicinal plants from 29 different families used for the treatment and prevention of respiratory system disorders (for cough mostly, 51.70% of all indications). Twenty eight out of 60 plant species were not included in the European Medicines Agency monographs and only 50% of all included species were used as indicated by the European Medicines Agency for respiratory system disorders. The trends in the ethnopharmacological choices of modern consumers and the analysis of archival sources can be a great source of ideas for new herbal-based pharmaceutical preparations for COVID-19 symptoms in Lithuania considering the safety recommendations.

Maoto, a traditional herbal medicine, for post-exposure prophylaxis for Japanese healthcare workers exposed to COVID-19: A single center study.

BACKGROUND: Little research has been done on post-exposure prophylaxis (PEP) for COVID-19. This study was done to determine if maoto, a traditional herbal medicine commonly used for diseases with symptoms similar to those of COVID-19, can be repurposed for post-exposure prophylaxis to prevent the spread of nosocomial infection with SARS-CoV-2. METHODS: A cohort analysis was done of the data of 55 health care workers (HCWs) whether to get infected with SARS-CoV-2 in a Japanese hospital experiencing a COVID-19 cluster in April of 2021. Of these subjects, maoto granules for medical use were prescribed for PEP to 42 HCWs and taken for three days in mid-April. Controls were 13 HCWs who rejected the use of maoto. Polymerase chain reaction was performed routinely once or twice a week or when a participant presented with symptoms of COVID-19. RESULT: There were no background differences between the maoto and control groups by profession, sex, or mean age. No severe adverse reactions were observed. During the observation period of 1 week, significantly fewer subjects were diagnosed with COVID-19 in the maoto group (N = 3, 7.1%) than in the control group (N = 6, 46.2%). The prophylactic effectiveness of maoto was 84.5%. CONCLUSION: Oral administration of maoto is suggested to be effective as PEP against nosocomial COVID-19 infection.

Herbal medicine for COVID-19: An overview of systematic reviews and meta-analysis.

BACKGROUND: As coronavirus disease 2019 (COVID-19) continues to spread throughout countries, researchers and scientific groups have published a large number of scientific papers examining effective treatments and prevention strategies for COVID-19, including herbal medicine. It has become difficult to navigate the increasing volume of scientific material on the pandemic, and critical appraisal of these outcomes is needed. This overview of systematic reviews (SRs) aims to synthesize evidence from SRs and summarize the effects of herbal medicine interventions in the treatment of COVID-19. METHODS: Four databases were searched from inception up to October 20, 2021. SRs analyzing primary studies of the efficacy of herbal medications for treating COVID-19 were included. Two reviewers selected the studies and retrieved the data independently. The AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews) was used to assess the methodological quality of the included SRs. RESULTS: A total of 21 SRs on herbal medicine treatments for COVID-19 were included. All SRs were published between May 2020 and September 2021. Thirteen of the SRs included only randomized controlled trials (RCTs), whereas the remaining eight included evidence from nonrandomized trials in addition to RCTs, with a significant overlap identified across the RCTs. Twelve SRs concluded that existing evidence was insufficient to form a definite judgment, nine found that herbal therapy was useful, and none indicated that herbal medicine had no benefit. The AMSTAR 2 tool revealed that the methodological quality of the included SRs was generally low. CONCLUSION: In this overview of SRs, we reviewed herbal medicine-related evidence from 21 SRs that were published after the outbreak of COVID-19. This study shows that while there is considerable evidence demonstrating the advantages of herbal medicine interventions, the quality of the evidence is inadequate to provide solid and accurate judgments about the effectiveness of herbal medicine therapies for COVID-19. Despite the crisis caused by the pandemic, clinical studies and SRs should comply with established methodological standards.

Prevention, treatment and potential mechanism of herbal medicine for Corona viruses: A review.

The pandemic of coronavirus disease 2019 (COVID-19) caused by the SARS-coronavirus 2(SARS-CoV-2) virus has become the greatest global public health crisis in recent years,and the COVID-19 epidemic is still continuing. However, due to the lack of effectivetherapeutic drugs, the treatment of corona viruses is facing huge challenges. In thiscontext, countries with a tradition of using herbal medicine such as China have beenwidely using herbal medicine for prevention and nonspecific treatment of corona virusesand achieved good responses. In this review, we will introduce the application of herbalmedicine in the treatment of corona virus patients in China and other countries, andreview the progress of related molecular mechanisms and antiviral activity ingredients ofherbal medicine, in order to provide a reference for herbal medicine in the treatment ofcorona viruses. We found that herbal medicines are used in the prevention and fightagainst COVID-19 in countries on all continents. In China, herbal medicine has beenreported to relieve some of the clinical symptoms of mild patients and shorten the length of hospital stay. However, as most herbal medicines for the clinical treatment of COVID-19still lack rigorous clinical trials, the clinical and economic value of herbal medicines in theprevention and treatment of COVID-19 has not been fully evaluated. Future work basedon large-scale randomized, double-blind clinical trials to evaluate herbal medicines andtheir active ingredients in the treatment of new COVID-19 will be very meaningful.

Perspectives on COVID-19 prevention and treatment using herbal medicine in Vietnam: A cross-sectional study.

Introduction: The significance of herbal medicine (HM) during the COVID-19 pandemic has been confirmed. Nevertheless, limited studies have included the people perspectives on COVID-19 prevention/treatment using herbal medicine in Vietnam. Thus, this study tackled the aforementioned issue. Methods: Online-based cross-sectional study was conducted in Vietnamese adults between February-April 2021. Descriptive analysis, regression and Chi-squared tests were implemented for the statistical purposes. Results: total of 787 respondents attended the study, 368 (46.8%) confirmed that they use herbal medicine/nutritional supplements for COVID-19 prevention/treatment. Over 50% of the respondents possessed positive perspective on vitamin C ingestion. Using herbal medicine for external use as a disinfectant was mostly preferred. Respondents who had a 'very good' health self-perception or who lived in rural areas, were more likely to have a positive opinion in the COVID-19 prevention/treatment using herbal medicine. The main barrier for herbal medicine utilization was the deficiency of personal experience or expert advice. Conclusion: The Vietnamese people commonly utilize herbal medicine for the COVID-19 prevention/treatment. These data might help policy-makers in managing the public knowledge and practice on herbal medicine use in Vietnam.

Phytometabolite profiling of Coronil, a herbal medicine for COVID-19, its identification by mass-spectroscopy and quality validation on liquid chromatographic platforms.

Coronil is a tri-herbal medicine consisting of immunomodulatory herbs, Withania somnifera, Tinospora cordifolia, and Ocimum sanctum. The formulation has been developed specifically as the supporting measure for COVID-19. Current investigation is aimed to identify the phytoconstituents in Coronil utilizing ultra-performance liquid chromatography-mass spectrometry coupled with quadrapole time of flight and to establish its quality standardization using high-performance liquid chromatography and high performance thin layer chromatography. Out of 52 identified compounds, cordifolioside A, magnoflorine, rosmarinic acid, palmatine, withanoside IV, withanoside V, withanone, betulinic acid, and ursolic acid were quantified in 15 different batches of Coronil on validated high-performance liquid chromatography method. Similarly, withanoside IV, withaferin A, magnoflorine, palmatine, rosmarinic acid, and ursolic acid were analyzed on high performance thin layer chromatography. Methods were validated as per the International Council for Harmonization guidelines. These methods were specific, reproducible, accurate, precise, linear (r2 > 0.99), and percent recoveries were within the prescribed limits. The content uniformity of Coronil was ascertained using Fourier transform infrared spectroscopy. Results indicated that, validated methods were fit for their intended use and the analytical quality of Coronil was consistent across the batches. Taken together, these developed methods could drive the analytical quality control of herbal medicines such as Coronil, and other formulations containing similar chemical profiles.

Leveraging knowledge of Asian herbal medicine and its active compounds as COVID-19 treatment and prevention.

The outbreak of COVID-19 disease has led to a search for effective vaccines or drugs. However, insufficient vaccine supplies to meet global demand and no effective approved prescribed drugs for COVID-19 have led some people to consider the use of alternative or complementary medicines, such as traditional herbal medicine. Medicinal plants have various therapeutic properties that depend on the active compounds they contain. Obviously, herbal medicine has had an essential role in treatment and prevention during COVID-19 outbreak, especially in Asian cultures. Hence, we reviewed the uses of herbal medicine in Asian cultures and described the prominent families and species that are sources of antiviral agents against COVID-19 on the basis of case reports, community surveys, and guidelines available in the literature databases. Antiviral efficacy as determined in laboratory testing was assessed, and several promising active compounds with their molecular targets in cell models against SARS-CoV-2 viral infection will be discussed. Our review findings revealed the highly frequent use of Lamiaceae family members, Zingiber officinale, and Glycyrrhiza spp. as medicinal sources for treatment of COVID-19. In addition, several plant bioactive compounds derived from traditional herbal medicine, including andrographolide, panduratin A, baicalein, digoxin, and digitoxin, have shown potent SARS-CoV-2 antiviral activity as compared with some repurposed FDA-approved drugs. These commonly used plants and promising compounds are recommended for further exploration of their safety and efficacy against COVID-19.

Green products from herbal medicine wastes by subcritical water treatment.

Herbal medicine wastes (HMWs) are byproducts of medicine factories, which are mainly landfilled for their environmental problems. Only bearing in mind the contamination and concerns caused by the COVID-19 pandemic and environmental emissions, the worth of herbal medicine wastes management and conversion to green products can be understood. In this work, subcritical water treatment was carried out batch-wise in a stainless tube reactor in the pressure range of 0.792-30.0 MPa, varying the temperature (127-327 °C) and time (1-60 min) of extraction. This resulted in new and green material sources, including organic acids, amino acids, and sugars. Amazingly, at very low extraction times (below 5 min) and high temperatures (above 277 °C), about 99% of HMWs were efficaciously converted to clean products by subcritical hydrothermal treatment. The results of hydrothermal extraction after 5 min indicated that at low temperatures (127-227 °C), the total organic carbon in the aqueous phase increased as the residual solid phase decreased, reaching a peak around 220 °C. Acetone soluble extracts or fat phase appeared above 227 °C and reached a maximum yield of 21% at 357 °C. Aspartic acid, threonine, and glycine were the primary amino acids; glycolic acid, formic acid, lactic acid, and acetic acid were obtained as the main organic acids, glucose, fructose, and cellobiose were substantial sugars produced from the aqueous phase after 5 min of hydrothermal subcritical hydrolysis extraction.

Dietary supplements and herbal medicine for COVID-19: A systematic review of randomized control trials.

BACKGROUND: The world is currently struggling with the Coronavirus disease 2019 (COVID-19) pandemic. Dietary supplements (DSs) and herbal medicine provide a potentially convenient and accessible method for its recovery, but direct evidence is limited. OBJECTIVE: This study aims to investigate the effectiveness of DSs and herbs in patients with COVID-19. METHODS: A systematic literature search was conducted in multiple electronic English and Chinese databases. Randomized controlled trials (RCTs) involving DSs or herbal medicine interventions on patients with COVID-19 from November 2019 to February 2021 were included. Data was extracted, summarized and critically examined. RESULTS: Out of 9402 records identified in the initial search, twelve RCTs were included in this review. Risk of bias of these RCTs was deemed high. Most of the trials were of low methodologic quality. Nine studies showed herbal supplements were beneficial to the recovery of COVID-19 patients; zinc sulfate could shorten the duration of loss of smell but not total recovery from COVID-19. No severe adverse events were reported. CONCLUSION: Herbal supplements may help patients with COVID-19, zinc sulfate is likely to shorten the duration of olfactory dysfunction. DS therapy and herbal medicine appear to be safe and effective adjuvant therapies for patients with COVID-19. These results must be interpreted with caution due to the overall low quality of the included trials. More well-designed RCTs are needed in the future.

Nanotechnology-based Herbal Formulations: A Survey of Recent Patents, Advancements, and Transformative Headways.

Nanotechnology in association with herbal medicine can lead to enhanced therapeutic and diminished adverse effects of medication. In turn, it can lead to synergistic effects of administered compound overcoming its demerits. Nowadays, the trend of herbal compounds to treat even a small illness is gaining momentum. Gone are the days when the ineffectiveness of a compound was impossible to be dealt with. Nevertheless, in this competitive era of science and innovative technology, it has become possible to maximize the usefulness of ineffective yet potent herbal compounds. The demand for herbal compounds is getting amplified because of their ability to treat a myriad of diseases, including COVID-19, showing fewer side effects. The merger of nanotechnology with traditional medicine augments the potential of herbal drugs for devastating dangerous and chronic diseases like cancer. In this review article, we have tried to assimilate the complete information regarding the use of different nanocarriers to overcome the drawbacks of herbal compounds. In addition, all the recent advancements in the herbal field, as well as the future exploration to be emphasized, have been discussed.

Molecular Basis of the Therapeutical Potential of Clove (Syzygium aromaticum L.) and Clues to Its Anti-COVID-19 Utility.

The current COronaVIrus Disease 19 (COVID-19) pandemic caused by SARS-CoV-2 infection is enormously affecting the worldwide health and economy. In the wait for an effective global immunization, the development of a specific therapeutic protocol to treat COVID-19 patients is clearly necessary as a short-term solution of the problem. Drug repurposing and herbal medicine represent two of the most explored strategies for an anti-COVID-19 drug discovery. Clove (Syzygium aromaticum L.) is a well-known culinary spice that has been used for centuries in folk medicine in many disorders. Interestingly, traditional medicines have used clove since ancient times to treat respiratory ailments, whilst clove ingredients show antiviral and anti-inflammatory properties. Other interesting features are the clove antithrombotic, immunostimulatory, and antibacterial effects. Thus, in this review, we discuss the potential role of clove in the frame of anti-COVID-19 therapy, focusing on the antiviral, anti-inflammatory, and antithrombotic effects of clove and its molecular constituents described in the scientific literature.

Turning Up the Volume for Precision Herbal Medicine in Africa in an Era of COVID-19 and Planetary Biodiversity Loss.

What would it take in terms of the structural reforms in science, technology, and culture to cultivate sustainable therapeutic and preventive medicine innovations against zoonotic infections such as coronavirus disease 2019 (COVID-19) in the 21st century? In May 2019, the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services warned that "around one million animal and plant species are now threatened with extinction." Biodiversity is essential for drug discovery and development. We are currently facing a dual challenge in therapeutics innovation with COVID-19 and loss in planetary biodiversity. Hence, there is an urgent need for new ideas and strategies for drug discovery as well as repurposed drugs for the COVID-19 pandemic. To these ends, the existing scholarship in, and the field of precision herbal medicine provide an alternative source for discovery of novel therapeutics against the novel coronavirus. We propose that the application of precision herbal medicine in Africa could usefully contribute to current efforts for therapeutics innovation for the COVID-19 pandemic, and beyond. The pandemic calls for interdisciplinary dialogue and turning up the volume for precision herbal medicine in Africa, and importantly, in ways informed by robust systems science as well as broad public engagement to codesign medicines in the 21st century.

COVID-19 Pandemic in the Midst of Civil War: Planetary Health and Plant Omics Field Notes from Aden, Yemen.

As the coronavirus disease 2019 (COVID-19) pandemic is impacting on the entire planet, field notes from resource-limited settings are increasingly relevant, both instrumentally and normatively, due to codependency of world populations in the struggle against the pandemic. Yemen is an apt and timely example to illustrate the social and political determinants of planetary health and the ways in which they impact on health care and dignity of people in times of crisis as well as during elective medical care. Importantly, many local communities have deep knowledge of various plant resources that can be evaluated with guidance of the omics systems science. The planetary society would be well poised to build resilience against future pandemics and ecological crises by harnessing local and global expertise in plant omics.

Antiviral Essential Oils Incorporated in Nanocarriers: Strategy for Prevention from COVID-19 and Future Infectious Pandemics.

BACKGROUND: Coronavirus has become a life-threatening disease and it is caused by severe acute respiratory syndrome (SARS). This new strain of coronavirus is not completely understood and to date, there is no treatment for coronavirus. Traditional ayurvedic medicines, mainly essential oils and Chinese herbs, have always played a vital role in the prevention and treatment of several epidemics and pandemics. In the meantime, guidelines of the ministry of AYUSH (Ayurveda, yoga, unani, siddha and homoepathy) include a traditional medicinal treatment for flu and fever and also recommended to boost immunity to prevent the spread of coronavirus. It is not possible to find which essential oil will offer the best level of protection. However, it is likely to assume that some essential oils are likely to offer a measurable level of defense in the same way they do with many other known viruses. METHODS: Literature relevant to various essential oils having antiviral activity has been collected and compiled. Various nanocarriers of essential oils have also been stated. The database was collected using various search engines such as J-Gate, Google Scholar, Sci-Hub, PubMed, ScienceDirect, etc. Results: Essential oils contain active constituents such as phenolic compounds, terpenoids, alkaloids, phenyl propanoids, etc., which are responsible for their biological properties such as antiviral, antibacterial, antimicrobial, antioxidant activities and many more. However, the use of essential oils has always been limited due to poor solubility, solvent toxicity, volatility and low solubility. Many nanotechnology based carriers especially, liposomes, dendrimers, nanoparticles, nanoemulsion and microemulsion, etc. have been evidenced to overcome limitations associated with essential oils. CONCLUSION: Several essential oils possess potent antiviral activity and are characterized by fewer side effects and are safe for human use. The nanocarrier systems of these oils have proved the potential to treat viral and bacterial infections. Lay Summary: Current COVID-19 era demands traditional treatment for immunity boost up as support therapy. Traditional ayurvedic medicines, mainly essential oils and Chinese herbs, have always played a vital role in the prevention and treatment of several epidemics and pandemics. Therefore, authors have summarized various essential oils having antiviral activity in current manuscript. Various nanocarriers of essential oils have been reported. Essential oils contain active constituents such as phenolic compounds, terpenoids, alkaloids, phenyl propanoids, etc., which are responsible for their biological properties such as antiviral, antibacterial, antimicrobial, antioxidant activity. However, the use of essential oils has always been limited due to poor solubility, solvent toxicity, volatility and low solubility. Many nanotechnology based carriers especially, liposomes, dendrimers, nanoparticles, nanoemulsion and microemulsion, etc. have been evidenced to overcome limitations associated with essential oils. The nanocarrier systems of these oils have proved the potential to treat viral and bacterial infections.

Evaluation of dietary supplement, functional food and herbal medicine use by dietitians during the COVID-19 pandemic.

OBJECTIVE: The current study was conducted to evaluate the dietary habits of the dietitians who had a leading role in this regard during the pandemic and their use of dietary supplements, functional food and herbal medicines. DESIGN: A cross-sectional study. An online questionnaire was used as a data collection tool to identify the participants' socio-demographic characteristics, health statuses and dietary habits and their use of dietary supplements, functional foods and herbal medicines. SETTING: Turkey. PARTICIPANTS: The study population was 550 dietitians. RESULTS: In the current study, the participants' average age was 30·6 ± 9·1 years, and most of them (88·2 %) were women. More than half of the participants (88·9 %) thought that adequate and balanced nutrition would positively affect the course of COVID-19. To avoid COVID-19, 94·5 % of the dietitians used dietary supplements, 46·1 % herbal medicines and 34·9 % functional foods during the pandemic. The most commonly used dietary supplement was fish oil (81·9 %), functional food was vegetables and fruits (80·5 %) and the herbal medicine was cinnamon (63·5 %). Women's consumption of functional foods was approximately twice higher compared with men (95 % Cl: 1·048, 4·165; P < 0·05). The findings showed that the longer the dietitians were in their careers, the more functional foods and herbal medicines they used. CONCLUSION: During the pandemic, dietitians' use of foods with protective effects against diseases increased depending on their academic knowledge and experience in nutrition. The findings obtained in the current study suggest that an expert's opinion should be obtained before using dietary supplements and herbal medicines.

In Silico Screening of Natural Products Isolated from Mexican Herbal Medicines against COVID-19.

The COVID-19 pandemic has already taken the lives of more than 2 million people worldwide, causing several political and socio-economic disturbances in our daily life. At the time of publication, there are non-effective pharmacological treatments, and vaccine distribution represents an important challenge for all countries. In this sense, research for novel molecules becomes essential to develop treatments against the SARS-CoV-2 virus. In this context, Mexican natural products have proven to be quite useful for drug development; therefore, in the present study, we perform an in silico screening of 100 compounds isolated from the most commonly used Mexican plants, against the SARS-CoV-2 virus. As results, we identify ten compounds that meet leadlikeness criteria (emodin anthrone, kaempferol, quercetin, aesculin, cichoriin, luteolin, matricin, riolozatrione, monocaffeoyl tartaric acid, aucubin). According to the docking analysis, only three compounds target the key proteins of SARS-CoV-2 (quercetin, riolozatrione and cichoriin), but only one appears to be safe (cichoriin). ADME (absorption, distribution, metabolism and excretion) properties and the physiologically based pharmacokinetic (PBPK) model show that cichoriin reaches higher lung levels (100 mg/Kg, IV); therefore, it may be considered in developing therapeutic tools.

Structure-based lead optimization of herbal medicine rutin for inhibiting SARS-CoV-2's main protease.

Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic with very limited specific treatments. To fight COVID-19, various traditional antiviral medicines have been prescribed in China to infected patients with mild to moderate symptoms and received unexpected success in controlling the disease. However, the molecular mechanisms of how these herbal medicines interact with the SARS-CoV-2 virus that causes COVID-19 have remained elusive. It is well known that the main protease (Mpro) of SARS-CoV-2 plays an important role in maturation of many viral proteins such as the RNA-dependent RNA polymerase. Here, we explore the underlying molecular mechanisms of the computationally determined top candidate, namely, rutin which is a key component in many traditional antiviral medicines such as Lianhuaqinwen and Shuanghuanlian, for inhibiting the viral target-Mpro. Using in silico methods (docking and molecular dynamics simulations), we revealed the dynamics and energetics of rutin when interacting with the Mpro of SARS-CoV-2, suggesting that the highly hydrophilic rutin molecule can be bound inside the Mpro's pocket (active site) and possibly inhibit its biological functions. In addition, we optimized the structure of rutin and designed two more hydrophobic analogs, M1 and M2, which satisfy the rule of five for western medicines and demonstrated that they (M2 in particular) possess much stronger binding affinities to the SARS-COV-2s Mpro than rutin, due to the enhanced hydrophobic interaction as well as more hydrogen bonds. Therefore, our results provide invaluable insights into the mechanism of a ligand's binding inside the Mpro and shed light on future structure-based designs of high-potent inhibitors for SARS-CoV-2 Mpro.