key: cord-0718708-73lokiyy authors: Yalçın, Serap; Yalçınkaya, Seda; Ercan, Fahriye title: In silico detection of inhibitor potential of Passiflora compounds against SARS-Cov-2(Covid-19) main protease by using Molecular Docking and Dynamic analyses date: 2021-05-04 journal: J Mol Struct DOI: 10.1016/j.molstruc.2021.130556 sha: 4eeb40789faa4d1c7596554db16b5f7ba7e4ff48 doc_id: 718708 cord_uid: 73lokiyy SARS-Cov-2(Covid-19) is a new strain of coronavirus and was firstly emerged in December 2019 in Wuhan, China. Now, there is no known specific treatment of Covid-19 available. COVID-19 main protease is a potential drug target and is firstly crystallised by Liu et al (2020). In the study, we investigated the drug potential of molecules that the components of an important medicinal plant Passiflora by using molecular docking, molecular dynamic and drug possibility properties of these molecules. Docking performances were done by Autodock. Chloroquine, hydroxychloroquine were used as standarts for comparison of tested ligands. The molecular docking results showed that the Luteolin, Lucenin, Olealonic acid, Isoorientin, Isochaphoside, Saponarin, Schaftoside etc.. ligands was bound with COVID-19 main protease above -8,0 kcal/mol binding energy. Besides, ADME, drug-likeness features of compounds of Passiflora were investigated using the rules of Lipinski, Veber, and Ghose. According to the results obtained, it has been shown that compounds of Passiflora have the potential to be an effective drug in the COVID-19 pandemic. Further studies are needed to reveal the drug potential of these ligands. Our results will be a source for these studies. Passiflora (passion flowers) is the largest genus of the family Passifloraceae. The species of this genus are distributed tropical regions of the World [1] . Many species of this genus have been found that contain anti-depressant properties. The leaves and the roots are generally more potent and have been used to improve the actions of mind-altering drugs. Few species of Passiflora have been studied according to its medicinal utility [2] . However, these plants have a major source of pharmacologically active compounds, including cytolysins, potential bactericid and anticancer drugs. For example, Passiflora quadrangularis is known with antihelminthic action and also often used to treat bronchitis, asthma, and whooping cough [3] . The new coronavirus type SARS-Cov 2 (severe acute respiratory syndrome), that appeared in December 2019 in China and became a global pandemic. There is not any specific treatment available so far. The viral particles effect both humans and animals, and can cause some serious infections of especially respiratory system. Besides, some drugs including chloroquine, remdesivir and hydroxychloroquine have been observed to be effective against Covid-19 [4] . Recent studies have shown that the genomic model of SARS-CoV 2 is comparable to other coronaviruses. It is stated that these viruses generally collect a few polypeptides in their life cycle and develop proteolytic degradation to produce 20 additional proteins. Among these proteases, it is emphasized that main protease (Mpro) and papain-like protease (PLpro) proteases are of vital importance in virus replication. Important studies have been done with these proteases to discover specific inhibitors against COVID-19. Yu et.al reported the calculation of the potential binding of luteolin and other natural components versus Mpro. It was concluded that luteolin also binds effectively with other target proteins of SARS-CoV-2 such as PLpro, Spike protein and RdRp [5] . An important therapeutic target for corona viruses is known to be the main protease , as this enzyme plays a key role in polyprotein processing and is active in a dimeric form [6] . Amin et al, 2021, stated that the main protease is the part of the replication machinery of the corona virus and can be used as a therapeutic target against the corona virus [7]. Li and Kang 2020, emphasized that the main protease encoded by the viral genome could be an attractive drug target, as it plays an important role in dividing viral polyproteins into functional proteins [8] In another study, it was noted that the sequence of the main protease is closely related to other betacoronaviruses and aids drug discovery studies based on previous lead compounds [9] . Ghosh et al., 2021, identified important molecular properties that regulate Mpro inhibitory properties [10] . All these studies reveal that the main protease is a suitable target for identifying potential drug substances. We also used the main protease in our study.Molecular docking is known a promising and useful tool for drug desing. In the present study, we investigated drug potential of Passiflora components against COVID-19 main (PDB ID: 6LU7). We aimed to find the most stable complex by revealing the binding energies. Molecular docking is known a promising and useful tool for drug desing. In the present study, we investigated drug potential of Passiflora components against COVID-19 main (PDB ID: 6LU7). We aimed to find the most stable complex by revealing the binding energies. Molecular docking calculations were performed in Autodock Vina software [11] . The water molecules and cofactors were removed from the protein to clearly see the protein-ligand interation [12] . COVID-19 main protease used as a protein and the structure of this protein was freely available from the RCSB Protein Data Bank as a 3D theoretical model (PDB ID: 6LU7). Twenty nine ligands were tested. Ligands that used in the study and their properties were given in Table 1 (https://pubchem.ncbi.nlm.nih.gov/). The binding potential of chloroquine and hydroxychloroquine has been reviewed as a control ligands. 2D structure of the ligands were converted to energy minimized 3D-structure. All protein and ligands were validated before performing the in silico computations [13]. The simulation of the ligand-protein complex was performed using the playmolecule software Currently, computer-based ADME analyses are gaining for drug discovery [20] . Pharmacokinetics and drug-likeness prediction of drug candidate molecule(s) was performed by online tool SwissADME Plant compounds have been always attractive from scientists to research novel drug development. (Fig 2, Fig 3 and Fig 4) . (Supplementery file). Drug-likeness can be characterized as a complex balance of different structural properties that determines whether a compound is a drug. These features, mainly lipophilicity, hydrogen bonding properties, molecule size, and pharmacophoric features and many others [29] . In addition, druglikeness results of compounds were shown in Table 3 . However, these inhibitors are a disadvantage as they tend to be toxic if they show off-target binding. Therefore, the presence of such inhibitors should be considered in drug development [31] . Perforatum sp. used for many years as a medicinal plant for different treatments, has recently become popular with research for its different properties. This medicinal plant has become available since the beneficial effects it on human health. In our research based on this useful plant, the possibility of being used as a medicine in SARS-Cov-2 pandemic that our country and all countries of the world have been fighting for a long time has been investigated. Based on the results, it was concluded that Perforatum could be effective on SARS-Cov-2, but it is necessary to conduct laboratory tests in vitro and in vivo on animals and patients to approve their validity in inhibiting Covid-19. 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According to Lipinski's rule (Pfizer's rule, Lipinski's rule of five, RO5), the active drug has no more than one violation of the following properties including molecular weight(MW) ≤500, LogP ≤5,