key: cord-0909039-jvca7z9x authors: Pradhan, Surbhi; Dubey, R. C. title: Molecular docking of a bioactive compound of C. sinensis n-heptadecanol-1 with opportunistic fungi date: 2021-11-01 journal: Current Research in Green and Sustainable Chemistry DOI: 10.1016/j.crgsc.2021.100208 sha: 85063cc059e808cc15596f38ac63c4dc19bfe6e3 doc_id: 909039 cord_uid: jvca7z9x With the expansion of immune-impaired people during second wave of Covid-19 the case of mucormycosis and aspergillosis caused by different fungi such as Rhizopus oryzae, Candida albicans and Aspergillus niger arose in different states. The current study reveals the molecular interaction of ligand and protein to find the novel and natural drug. The molecular docking was carried out by CB-dock tool and the ligand compound n-heptadecanol-1 were docked with different protein of opportunistic fungi. The most significant outcomes were depicted against C. albicans (−4.6 kcal/mol) followed by R. oryzae (−3.9 kcal/mol) and A. niger (−3.0 kcal/mol). n-heptadecanol-1 showed therapeutic potential and eliminates the issue of drug inadequacy that could act as potential anti-fungal agent. Many fungal infections are known to infect the human body both externally and internally due to several reasons. One of the causes is the weak inherent immune system and immunocompromised people due to diabetes, AIDS and drug users, cancer patients and COVID-19 patients. In 2021, second wave of coronavirus surprisingly the COVID-19 patients were infected by fungal pathogens causing mucormycosis, opportunistic candidiasis and aspergillosis. At present, these opportunistic fungi have become more offensive to the COVID-19 patients and immunocompromised individuals. Several recent cases of mucormycosis have been observed worldwide with a mortality rate of approximately 80% (Ribes et al., 2000) . Mucormycosis is caused by the members of Mucorales e.g. the species of Mucor, Rhizopus, J o u r n a l P r e -p r o o f Rhizomucor and Absidia etc. Mucormycosis is characterized by nodular lesions and inflammation leading to tissues undergoing extensive bruise, formation of ulcers and finally proclamation. Existential and experimental evidences undeniable point to phagocytes play a significant role as the primary host defence against mucormycosis. People with an ultra-low of phagocyte number or impaired phagocyte function have a substantial risk for invasive mucormycosis infection. Normal and healthy immune cells, such as mononuclear cells and polymorphonuclear phagocytes readily take up and kill the hyphae and spores of the fungi that cause mucormycosis. Neutropenia induced by cytotoxic chemotherapy is also a well-known risk factor for mucormycosis (Waldorf et al., 1984) . Mucormycosis has a distinct proclivity for invasion of endothelial cells of the vascular system, and this ability is likely important in the propagation of disease from a primary site of infection (Riley et al., 2016) . Mucormycosis cause infection such as gastrointestinal tract, pulmonary infection, cutaneous, rhino-orbital cerebral infection cause in diabetic and organ transplant persons and immunosuppressive people (Riley et al., 2016) . Among patients with COVID-19 who require hospitalisation, many suffer from severe respiratory distress syndrome, are admitted to an ICU and are exposed to various factors associated with candidemia (Eggimann et al., 2003) . Therefore, candidemia could be a potential complication of patients with COVID-19 cared in ICUs. In Italy reported 21 cases of candidemia in patients with COVID-19 and found a higher incidence of candidemia in COVID-19 patients compared with a historical cohort (Nucci et al., 2021) . Similarly, in India patients are also endure from fatal disease Candiasis. Aspergillus genus is known for causing invasive pulmonary aspergillosis (IPA) as a common complication in patients with severe respiratory affliction and high mortality rates is also increased (Trovato et al., 2021) . There are many incline factors to the development of IPA, basically recognized in protracted treatment with corticosteroids and lung epithelial damage J o u r n a l P r e -p r o o f (Mohamed et al., 2020) . Several cases of IPA have been documented as super-infections in patients with severe respiratory illness such as influenza and MERS-CoV (Koehler et al., 2020) . Starting in December 2019 many severe respiratory syndrome cases caused by Coronavirus-19 (SARS-CoV-2) have been diagnosed. The clinical impact of this infection defines a highly dysregulated immune response and diffuse lung damage, which lead to the early onset of secondary infections. Here we describe a case of invasive pulmonary aspergillosis by Aspergillus niger in a patient with COVID-19 pneumoniae and acute respiratory distress syndrome. The antifungals comprise Amphotericin B, Echinocandins and Posaconazole that are nephrotoxic and hepatotoxic (Chayakulkeeree et al., 2006) . The drugs are mostly used synergistically, but owing to the emergence of drug-resistant fungal strains, their varied sensitivity towards antifungal agents (Gupta et al., 2011) . Due to the more use of anti-fungal drugs and therapies, the microorganisms show resistance regarding these drugs. Therefore, medicinal plants play a significant role to overcome such complications. Camellia sinensis is the medicinal plant having antimicrobial and antioxidant property due to the presence of active compounds such as flavonoids, terpenoids, tannins, saponins and alkaloids (Pradhan and Dubey, 2020) . So, the utilize of C. sinensis to impede the fungal growth. This research article focuses on the antifungal activity of bioactive compounds extracted from Camellia sinensis against opportunistic fungi. The bioactive compound (ligand) n-heptadecanol-1 was procured from our previous results of GC-MS analysis (Pradhan and Dubey, 2021) . The crystal structure of compounds was obtained from the PubChem database (n-heptadecanol-1). The protein structure of ALS-3 of Candida albicans, G-6-P of Rhizopus oryzae and Est A J o u r n a l P r e -p r o o f of Aspergillus niger was obtained from Protein Data Bank (PDB, https://www.rcsb.org/), the high-resolution model was selected. Then, the docking was performed by the CB-Dock tool (Yang et al., 2019) . The n-heptadecanol-1 was docked with proteins of various opportunistic and pathogenic fungi. n-heptadecanol-1 was docked with protein of R. oryzae by CB-dock blind tool, which aids in predicting the exquisite binding position of ligand and protein. The generating expounding of protein-ligand binding is explicable for its activity. The binding affinity was found -3.9 kcal/mol. Similarly, the same compound binds with the protein of C. albicans, and A. niger the binding affinity was found -4.6 kcal/mol and -3.0 kcal/mol. The best binding affinity of protein was exhibited with C. albicans followed by R. oryzae and A. niger. Among these bioactive compounds, n-heptadecanol-1 was found more potent in our previous study. This compound is known for its antimicrobial and anti-inflammatory activity (Chavan et al., 2010; Pradhan and Dubey, 2021) . Therefore, n-heptadecanol-1 was used as a ligand to identify the potential of the compound as an anti-fungal drug discovery. Molecular docking is the computational technique to determine the potency of any compound that is used as a drug for prospects. Similarly, n-heptadecanol is docked with the protein of opportunistic fungi that infects immunocompromised people and nowadays especially covid patients. R. oryzae is the main causative agent of mucormycosis. The study of germination conidia and adherence to plastic revealed that attachment occurred before germination and decreased dramatically with germ tube formation. This relates to the important moderation of the cell wall of the fungus concerning both carbohydrate composition and distribution of anionic sites. Furthermore, the attachment of spores to extracellular matrix components immobilized onto wells of polystyrene microtiter plates has been investigated. Spores adhered readily to immobilized laminin or type IV collagen, but not to fibronectin or the glycosaminoglycans. The immunofluorescence technique revealed that laminin and type IV collagen interacted exclusively with spores and mother cells of germ tubes. Thus, the identification of laminin or collagen by spores may participate in their adherence to epithelial basement membranes exposed after epithelial tissue damage which frequently accompanies the predisposing factors for mucormycosis (Bouchara et al., 1996) . It was reported that C. sinensis have polyphenols that depicted anti-fungal potential against the species of Rhizopus and Candida (Yang and Xiang, 2015) . In our study, the protein of R. oryzae docked with ligand (n-heptadecanol-1) depicted good docking outcomes and can inhibit the growth of R. oryzae. So, it is an effective J o u r n a l P r e -p r o o f and natural way to impede the growth of R. oryzae. The binding affinity was found -3.9 kcal/mol. C. albicans play a role in normal human flora, and it grows on mucosal surfaces in well-being individuals. In susceptible and immune impaired hosts, these fungi can cause both hematogenous and mucosal and disseminated ailment. It persists in the host tissue and induces disease, it must be capable to attach both biotic and abiotic surfaces, invade host cells, and acquire iron for growth. The C. albicans hypha-specific surface protein Als3 is a member of the agglutinin-like sequence (Als) family of proteins and is important for adhesion and invasion. Functioning as an adhesin, Als3 mediates attachment to epithelial cells, endothelial cells, and extracellular matrix proteins. It also plays a significant role in biofilm formation on prosthetic surfaces, both alone and in mixed infection with S. gordonii. Als3 is one of two known C. albicans invasions. It binds to host cell receptors such as E-cadherin and N-cadherin and thereby induces host cells to endocytose the organism. Als3 also binds to host cell ferritin and enables C. albicans to utilize this protein as a source of iron. Because of its multiple functions and its high expression level. In vivo, Als3 is a promising target for vaccines that induce protective cell-mediated and antibody responses. In our study, we target this protein (Als3) to inhibit the activity of C. albicans that are harmful to immunocompromised people. The protein of C. albicans docked with ligand showed remarkable outcomes. It showed good binding affinity -4.6 kcal/mol energy. Antifungal activity was also reported against C. albicans (Yoon et al., 2005) . In our previous study, n-heptadecanol-1 showed a good zone of inhibition against C. albicans (Pradhan and Dubey, 2021) . Aspergillus niger is a non-pathogenic opportunistic fungus, even though patients with a record of severe ailment and immunocompromised treatment can favour the growth of fungi. It is an J o u r n a l P r e -p r o o f opportunistic human pathogen and important for its epidemiological studies. It causes deadly fungal air-borne infection in advanced countries known as invasive pulmonary aspergillosis, a fatal disease caused by mycosis-infected immunocompromised people (Bourne et al., 2004) . At present time, these fatal fungi also infect the immunocompromised covid patients and show their severe and deadly symptoms. EstA is a protein and remarkable to its specificity towards short acyl chain substrate and recognized as a new member of fungal esterases within the α/β hydrolase super protein of family that causes pathogenicity. The outcomes of our study depicted good binding affinity is -3.0 kcal/mol. Therefore, it has been proved that the compound procured from C. sinensis it is effective and able to impede the growth of such opportunistic fungi and replaces the synthetic antifungal drug. As per our knowledge, this is the first report and such study has not been done by anyone so far. Nowadays the opportunistic fungi are becoming fatal for immunocompromised patients which the COVID-19 cases increasing with several wave. The increasing incidence and severity of invasive fungal mycoses have led to new and natural anti-fungal strategies aimed to reinstate synthetic drugs. Our study showed an alternatives and substitute ways to shut down the growth and development of opportunistic fungi effectively. 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