key: cord-1005658-ee0vjzs0 authors: Thakkar, Sampark S.; Shelat, Foram; Thakor, Parth title: Magical bullets from an indigenous Indian medicinal plant Tinospora cordifolia: An in silico approach for the antidote of SARS-CoV-2 date: 2021-02-23 journal: nan DOI: 10.1016/j.ejpe.2021.02.005 sha: a7557cce7f2f9fb989a56c97f4da1d70db925d66 doc_id: 1005658 cord_uid: ee0vjzs0 World Health Organization declared COVID-19 as a global pandemic. A diverse array of drugs failed to combat. There is an immense need for novel lead molecules. Medicinal plants are the reservoir of secondary metabolites. In silico approach has been carried out to dock the ligands (various secondary metabolites from Tinospora cordifolia) to the target (SARS-CoV-2 main protease) and compared its efficacy against standard drugs (Azithromycin, Chloroquine, Hydroxychloroquine, Favipiravir, Remdesivir). In silico molecular docking approach provides insight into the screened molecules that might prove to be an effective inhibitor for SARS-CoV-2. Out of five standard drug molecules, two widely used antiviral drugs (Favipiravir and Remdesivir) are ascribed as the most potent molecules based on their highest docking score in the present study. Columbin, Tinosporide, N-trans-feruloyl-tyramine-diacetate, Amritoside C, Amritoside B, Amritoside A, Tinocordifolin, Palmatoside G, Palmatoside F, and Maslinic acids are other molecules considered to be the key molecules based on their docking score (range between -5.718 to -5.020). is bestowed with an enormous diversity of plants on this earth due to it is rightly called a ''botanical garden of the world'' [14] . To fight against the COVID-19, the Ayush Department of India is going to start the clinical trials on COVID patients with the cocktail of four Ayurveda medicines, Tinospora cordifolia is one of them. T. cordifolia (Willd.) Miers ex Hook. f. & Thoms is a miraculous plant that belongs to the family Menispermaceae. It is also known by diverse names Guduuchi, Guduuchikaa, Guluuchi, Amrita, Amritalataa, Amritavalli, Chinnaruuhaa, Chinnodbhavaa, Madhuparni, Vatsaadani, Tantrikaa, Kundalini, Guduchi sattva in Ayurveda, and Giloya in folk. Furthermore, this plant is also known as the herbal ingredient of "soma" or "heavenly elixir" (food for immortals, mentioned in Rigveda) among altogether more than 100 herbal ingredients [15] [16] [17] . T. cordifolia is also known as ''nectar of life'', as it strengthens the immune system of the body and maintains the functions of its various organs in harmony [18] . T. cordifolia is a large, glabrous, deciduous, climbing shrub found in the tropical region of India, Andamans, China. The structure of the stem is fibrous and the transverse section exhibits a yellowish wood with radially arranged wedge-shaped wood bundles, containing large vessels, separated by narrow medullary rays. It has creamy-white to grey bark, deeply left spirally and the stem contains rosette-like lenticels. The leaves are membranous and cordate in shape. Flowers are in axillary position, 2-9 cm long raceme on leaflet branches, unisexual, small, and yellow. Male flowers are clustered and female is usually solitary. The seeds are curved. Fruits are fleshy and single-seeded. Flowers grow during the summer and fruits during the winter [19] [20] [21] . It is rightly said that 'the substance never dies', each part of the plant was reported for their notwithstanding activity (Fig. 2) . T. cordifolia has several therapeutic properties. It has been reported for various biological activities including such as jaundice, rheumatism, urinary disorder, skin diseases, diabetes, anemia, inflammation, allergic condition, anti-periodic, radioprotective properties, etc. The root of Giloya (T. cordifolia) is used as a potent emetic and for bowel obstruction. The starch of this plant has a potential household remedy for chronic fever, relieves burning sensation, increases energy and appetite. Moreover, it is also useful in the treatment of helminthiasis, heart diseases, leprosy, and rheumatoid arthritis, support the immune system, the body's resistance to infections, supports standard white blood cell structure, function, and levels. It also helps in digestive ailments such as hyperacidity, colitis, worm infestations, loss of appetite, abdominal pain, excessive thirst, and vomiting, and even liver disorders like hepatitis [22] [23] [24] [25] [26] [27] [28] . Very few protein crystal structures are available in the protein databank for SARS-CoV-2. SARS-CoV-2 main protease, a potential drug target, crystal structure (PDB-ID: 6Y84) was selected and used for docking study. SARS-CoV-2 main protease is considered to be a key for the survival of the virus and its growth [29] . In the present study, we have utilized the prior knowledge on the different secondary metabolites reported from the T. cordifolia a potent Indian medicinal plant for their medicinal values, and tried to explore whether any of the screened metabolites can be used as novel agents for controlling SARS-CoV-2 or not through in silico study. In the present study, we have performed the literature review and shortlisted the compounds from T. cordifolia which were commonly reported for their known biological activities. We have prepared a list of 20 chemical compounds from T. cordifolia and 05 standard drugs used for the treatment of SARS-CoV-2 (Table-1 The absorption, distribution, metabolism, and excretion were predicted for all compounds using the QikProp tool (Schrödinger Maestro 11.8, Release 2018-4). QikProp is a quick, accurate, easy-to-use ADME prediction program that predicts physically significant descriptors and pharmaceutically relevant properties of molecules. ADME properties are a major cause of attrition in drug development. Optimization of these properties at the early stage of drug discovery may reduce the risk of failure in clinical trials [31-32]. Molecular docking calculations were completed using Schrodinger docking suits (Schrödinger Maestro 11.8, Release 2018-4) using standard precision. The protein SARS-CoV-2 main protease (PDB-ID: 6Y84) was prepared by re-strained minimization using force field OPLS3E. The grid site was created using Glide receptor grid generator with site coordinates (x = 11.96, y = -5.02, z = 19.07) and docking length of 20 Å (Fig. 3 ). Ligands were prepared using force field OPLS3E and possible states were generated from pH 7.0 ± 2.0. Docking scores are reported in kcal/mol, the more negative the number, the better binding. Many potential therapeutic agents fail to the extent of the clinical trials due to their unfavorable absorption, distribution, metabolism, and elimination (ADME) parameters. Apart from ADME, drug likeliness property is another major parameter that affects clinical trials. The pharmacokinetic parameters are significant for an orally administered drug. This phase includes absorption from the gastrointestinal tract and is distributed to the various targets through the circulatory system of the body i.e. blood. Numerous factors affect the drug's survival in the body as it travels and is metabolized in the liver [33] . ADME prediction is performed to facilitate the creation of new drug molecules, the molecules of which must comply with the conditions of Lipinski's rule of five [34] . The results of this study are summarized in Table 2. Every molecule has a fixed number of non-conjugated amine groups. The range of this is fixed (0-2) ( Table 3) . Almost all the molecules and standard drugs are in this range except Azithromycin. Similarly, each molecule has a fixed number of amidine and guanidine groups, carboxylic acid groups, and non-conjugated amide groups according to their diverse chemical structure. All the secondary metabolites and standard drug molecules are fit in this range. Except for Remdesivir, all the compounds are in the range of several non-trivial (not CX3), non-hindered (not alkene, amide, small ring) rotatable bonds i.e. 0-15 [35]. The presence of reactive functional these groups can lead to false positives in high throughput screening assays and to decomposition, reactivity, or toxicity problems in vivo. The range of this is in the range of 0 to 2 ( Table 3) . Azithromycin, N-trans-feruloyl-tyramine-diacetate, Tinocordifolioside, Palmatoside F are the compounds in the present study which have 3 reactive functional groups. and Tinosporide violate the globularity parameter. All the molecules except Favipiravir follow the range of polarizability. Remdesivir is not in the range for the predicted hexadecane/gas partition coefficient. Amritoside B and Azithromycin are the two molecules, which do not follow the range of the predicted octanol/gas partition coefficient. Two molecules Phytol and Phytanic Acid are below the range for the predicted water/gas partition coefficient. All the molecules are in the range of the predicted octanol/water partition coefficient. Phytol is not following the predicted aqueous solubility (log S). Remdesivir is not in the range of CIQPlogS parameter (i.e. conformation-independent predicted aqueous solubility). QPlogHERG is the parameter, which predicts the IC 50 value that carried out the blockage of HERG K+ channels [39] . The entire standard drug molecules used in the present study except for Favipiravir and Tetrahydropalmatine, N-trans-feruloyl moieties are highly concerned molecules for HERG K+ channel activity. Caco-2 cells are a model for the gut-blood barrier. Caco-2 cell permeability is one of the parameters to check the gut-blood barrier capacity. Chloroquine, Columbin, Palmarin, Tetrahydropalmatine, Isocolumbin, Tinosporide, N-trans-feruloyl-tyraminediacetate, Tinocordifolin, Phytol have the greater chance to cross this barrier while Amritoside C, Amritoside B, Amritoside A have a poor capacity for crossing this barrier. All the molecules follow the range for the brain/blood partition coefficient [40]. This is one of the key properties of the drug molecule because it will not cross the blood-brain barrier and affect the Central Nervous System. MDCK cells have been considered as a good mimic for the blood-brain barrier. Chloroquine, Hydroxychloroquine, Tetrahydropalmatine, Tinocordifolin, and Phytol have shown higher MDCK cell permeability while Amritoside D, Amritoside C, Amritoside B, Amritoside A, Azithromycin, Tinosporaside, Palmatoside G, Palmatoside F have shown poor MDCK cell permeability. All the components showed good skin permeability, which was reflected through the QPlogKp. Except for Phytanic Acid, all the molecules showed the PM3 calculated ionization potential in the range ( Table 3) Chloroquine, Hydroxychloroquine, Columbin, Palmarin, Tetrahydropalmatine, Isocolumbin, Tinosporide, N-trans-feruloyl-tyramine-diacetate, N-trans-feruloyl-tyramine, Tinocordifolin, Phytol, Phytanic Acid, Maslinic Acid have shown more than 80% human oral absorption. Amritoside C, Amritoside B, and Amritoside A have shown poor human oral absorption i.e. less than 25% ( Table 3) . All molecules are in the range of the solvent-accessible surface area of fluorine atoms and amide oxygen atoms. Van der Waals surface area of polar nitrogen and oxygen atoms and carbonyl carbon atoms have slightly higher than in Amritoside C, Amritoside B than that of the maximum number (i.e. greater than 200). All the molecules follow Lipinski's rule of five. (i.e. mol_MW < 500, QPlogPo/w < 5, donorHB ≤ 5, accptHB ≤ 10) [33, 42]. Compounds that satisfy these rules are considered drug-like. Furthermore, all the compounds follow Jorgensen's rule of three. The three rules are: QPlogS > -5.7, QP PCaco > 22 nm/s, # Primary Metabolites < 7. Compounds with fewer (and preferably no) violations of these rules are more likely to be orally available. Stars parameter indicates that the number of properties or descriptor values that fall outside the 95% range of similar values for known drugs. The following properties and descriptors are included in the determination of stars: Molecular weight, dipole, IP, EA, SASA, FOSA, FISA, PISA, WPSA, PSA, volume, #rotor, donorHB, accptHB, glob, QPpolrz, QPlogPC16, QPlogPoct, QPlogPw, QPlogPo/w, logS, QPLogKhsa, QPlogBB, #metabol ( Table 3) . A large number of stars suggests that a molecule is less drug-like than molecules with few stars. All the compounds in the present studies reported for various biological activities including anti-HIV, antioxidant, anticancer, cytotoxicity, jaundice, rheumatism, urinary disorder, skin diseases, diabetes, anemia, inflammation, allergic condition, anti-periodic, radioprotective properties, etc. and all of them follow the range for the stars [22-28, 43-45]. The potential interactions of all 25 compounds (20 secondary metabolites from T. cordifolia and standard drugs) with the SARS-CoV-2 main protease (PDB-ID: 6Y84) have investigated through molecular docking studies (using Glide). Table 4 comprises the docking scores, Glide Emodel, and Glide energy. The docking score is the key parameter that reflects the favourable binding of the ligands to the target (SARS-CoV-2 main protease). Except for the Phytol, Hydroxychloroquine, Chloroquine, and Azithromycin, all the molecules in the present study have shown favourable binding with the target, which has reflected through the higher docking scores. The choice of best-docked structure for each ligand has made using a model energy score (i.e. Glide Emodel). The values of Glide Emodel suggest the best pose of a ligand docked with the target (SARS-CoV-2 main protease) ( Table 4) . Two widely used antiviral drugs Favipiravir and Remdesivir are the most potent molecules having the highest score. Columbin, Tinosporide, N-trans-feruloyl-tyramine-diacetate, Amritoside C, Amritoside B, Amritoside A, Tinocordifolin, Palmatoside G, Palmatoside F, and Maslinic acids are considered to be the key molecules based on the docking score range between -5.718 to -5.020 just slightly lower than that of the Favipiravir and Remdesivir. Molecules like Palmarin, Tetrahydropalmatine, Isocolumbin, N-trans-feruloyl-tyramine, Amritoside D, Tinocordiside, Tinocordifolioside, and Tinosporaside are the moderately active molecules with docking score in a range of -4.955 to -3.911 (Table 4) . For all the ligands, the proposed binding mode is consistent with that of the three amino acid residues viz. HIP 41, CYS 145, and HIE 164, key interaction points of the target (SARS-CoV-2 main protease) [29] . The key amino acid residues involved in the interactions with the target through the different bonds are shown in Table 5 . The graphical binding modes of all molecules and standard drugs are shown in Fig. 4 . Molecular modeling suggests that HIP 41 to be one of the most imperative amino acid residues for hydrogen bonding interaction. In the present study, this residue is forming the hydrogen bonds with diverse molecules including the Columbin, Palmarin, Isocolumbin, N-trans-feruloyl-tyramine, Amritoside D, Amritoside C, Amritoside B, Amritoside A, and two of the standard drugs Remdesivir, Hydroxychloroquine (Table 5, Fig. 4) . Predicted aqueous solubility, log S. S in mol dm −3 is the concentration of the solute in a saturated solution that is in equilibrium with the crystalline solid. −6.5 -0.5 Conformation-independent predicted aqueous solubility, log S. S in mol dm −3 is the concentration of the solute in a saturated solution that is in equilibrium with the crystalline solid. −6.5 -0.5 Predicted IC 50 value for blockage of HERG K + channels. concern below −5 <25 poor, QPPCaco Predicted apparent Caco-2 cell permeability in nm/sec. Caco-2 cells are a model for the gut-blood barrier. QikProp predictions are for nonactive transport. >500 great Predicted brain/blood partition coefficient. Note: QikProp predictions are for orally delivered drugs so, for example, dopamine and serotonin are CNS negative because they are too polar to cross the blood-brain barrier −3.0 -1.2 Predicted apparent MDCK cell permeability in nm/sec. MDCK cells are considered to be a good mimic for the blood-brain barrier. QikProp predictions are for non-active transport. >500 great Predicted skin permeability, log K p . −8.0 -−1.0 PM3 calculated ionization potential (negative of HOMO energy). 7.9 -10.5 EA(eV) PM3 calculated electron affinity (negative of LUMO energy). −0.9 -1.7 #metab Number of likely metabolic reactions. Prediction of binding to human serum albumin. −1.5 -1.5 Predicted qualitative human oral absorption: 1, 2, or 3 for low, medium, or high. The text version is reported in the output. The assessment uses a knowledge-based set of rules, including checking for suitable values of PercentHumanOralAbsorption, number of metabolites, number of rotatable bonds, logP, solubility and cell permeability. >80% is high Predicted human oral absorption on 0 to 100% scale. The prediction is based on a quantitative multiple linear regression model. This property usually correlates well with HumanOralAbsorption, as both measure the same property. Compounds with fewer (and preferably no) violations of these rules are more likely to be orally available. maximum is 3 Clinical characteristics of Coronavirus disease 2019 in China Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease Peptide-like and small-molecule inhibitors against Covid-19 Emerging coronaviruses: Genome structure, replication, and pathogenesis Clinical Virology Potential maternal and infant outcomes from coronavirus 2019-nCoV (SARS-CoV-2) infecting pregnant women: Lessons from SARS, MERS, and other human coronavirus infections Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19) Moroccan Medicinal plants as inhibitors against SARS-CoV-2 main protease: Computational investigations Severe Acute Respiratory Syndrome: Historical, Epidemiologic, and Clinical Features From SARS to MERS, thrusting coronaviruses into the spotlight Extraction and purification of phytol from Abutilon indicum: cytotoxic and apoptotic activity Investigation of novel apoptosis-inducing substances and their mode of action Indian medicinal plants-an illustrated dictionary Aqueous ethanolic extract of Tinospora cordifolia as a potential candidate for differentiation based therapy of glioblastomas Soma, food of the immortals according to the Bower Manuscript (Kashmir, 6th century AD) Extraction methods and bioautography for evaluation of medicinal plant antimicrobial activity Medicinal use of the unique plant Tinospora Cordifolia: evidence from the traditional medicine and recent research Medicinal and Beneficial Health Applications of Tinospora cordifolia (Guduchi): A Miraculous Herb Countering Various Diseases/Disorders and its Immunomodulatory Effects Tinospora cordifolia (Willd.) Hook. F.and Thomson-A plant with immense economic potential Tinospora cordifolia: its bioactivities & evaluation of physicochemical properties Immunomodulatory active compounds from Tinospora cordifolia Radioprotective potential of an herbal extract of Tinospora cordifolia Antidiabetic potential and identification of phytochemicals from Tinospora cordifolia Tinospora cordifolia (Guduchi) a reservoir plant for therapeutic applications Tinospora cordifolia: an antimicrobial and immunity enhancer plant Effect of leaf powder of giloy (Tinospora cordifolia) in fish feed on survival and growth of post larvae of Catla catla