key: cord-1005911-qxv45tll authors: Kumar Vishvakarma, Vijay; Nand, Bhaskara; Kumar, Vinod; Kumari, Kamlesh; Bahadur, Indra; Singh, Prashant title: Xanthene based Hybrid Analogues to inhibit protease of Novel Corona Virus: Molecular docking and ADMET studies date: 2020-10-21 journal: Comput Toxicol DOI: 10.1016/j.comtox.2020.100140 sha: 1439025cd636c7bd2e35f9ca4cedabce82ed5b10 doc_id: 1005911 cord_uid: qxv45tll In December, 2019, the SARS-CoV-2 was reported for the first time and the infected person is reported at Wuhan, China. Till date, about twenty four million people around the world are infected due to the SARS-CoV-2. The structure of this corona virus is new and different from other corona viruses. The genome has a positive sense single RNA strand and it is responsible for the encoding of the protein. The protease of the SARS-CoV-2 is responsible for the cleavage and therefore, it should be targeted to develop medicine. Till date, no medicine or vaccine is in the market to cure from the infection. Researchers around the world are working on the development of efficacious and safe vaccine/ drug to cure from the infection. Therefore, the authors used previously synthesized compounds, xanthene-triazole-chloroquinoline/ xanthene-chloroquinoline hybrids for the inhibition of the main protease of the SARS-CoV-2 via using computational tools, molecular docking and ADMET properties. COMD AP3 was found to be the best candidate from the library of the designed molecules. It has acceptable solubility along with the distribution and metabolism property. ADMET results corroborate the docking result towards the potency of COMP AP3. [Figure: see text] Keywords: Main protease of SARS-CoV-2; inhibition; docking; hybrids; ADMET Introduction Coronaviruses (CoVs) represents a class of viruses, affect human beings through zoonotic transmission. In the past two decades, this is the third incident of the manifestation of a novel coronavirus, after severe acute respiratory syndrome (SARS, causative agent SARS-CoV) in 2003 and middle-east respiratory syndrome (MERS causative agent MERS-CoV) in 2012. The emergence of COVID-19 from SARS-CoV-2 infection has been found for the first time in Wuhan, a city of the China and then spread throughout the world. Approximately twenty four million people around the world got infected due to the virus. It is a challenge for the world and also affected the health sector and economy globally. (Centor, Kim et al. 2020; Favalli, Biggioggero et al. 2020; Lim, Jeon et al. 2020; Moccia, Janiri et al. 2020; Ussher, Le Gros et al. 2020; Zhu, Lu et al. 2020 ) Reports advocates that SARS, SARS-CoV-2 use the angiotensin-converting enzyme 2 (ACE2) receptors for entry into the cell. This potentially unlocks the probability of using the same therapeutic approaches that were effective in blocking SARS. (Coffey, Moynagh et al. 2020; Couper, Taylor-Phillips et al. 2020; Ferner and Aronson 2020; Lentini, Cavalluzzi et al. 2020; Lovell, Maddocks et al. 2020; Sturrock and Chevassut 2020; Tal-Singer and Crapo 2020; Yuki, Fujiogi et al. 2020 ) Presently, there is no absolute and proven treatment, although numerous pharmacological options are being explored. Some of the trials which have been initiated include using baricitinib , lopinavir, ritonavir, darunavir, remdesivir, ribavirin, galidesivir, BCX-4430 (salt form of galidesivir), Arbidol, and nitazoxanide. (Ferner and Aronson 2020; Lentini, Cavalluzzi et al. 2020; Muralidharan, Sakthivel et al. 2020; Shah, Das et al. 2020; Sturrock and Chevassut 2020; Zheng, Tao et al. 2020) Researchers around the world have investigated the role of the choroquine in the treatment of infected people from SARS-CoV-2 and it is a proven anti-malarial drug. Further, it is considered to avoid the viral replication to cure the people from infection. (Abena, Decloedt et al. 2020; Ferner and Aronson 2020; Gendrot, Javelle et al. 2020; Moore 2020; Muralidharan, Sakthivel et al. 2020; Principi and Esposito 2020; Sturrock and Chevassut 2020; Verscheijden, van der Zanden et al. 2020) Literature reported the significance of the banzo[a]xanthene based molecules lots of biological application and proven to be promising anti-microbial, anti-malarial etc. These are heterocyclic molecules containing triazoles and quinoline motifs and play key role to make the compounds pharmacologically active. Triazoles are known for their biological activity in different areas i.e. antimicroabial, antiviral etc and the similar biological potency has been shown by the quinolines. (Albadi, Alihosseinzadeh et al. 2015; Li, He et al. 2015; Moura, de Almeida et al. 2016; Zhang, You et al. 2016; Song, Wang et al. 2019; Avena, Qiao et al. 2020; Bhattacharyya, Nandi et al. 2020 ) Formation of hybrid compounds is an interesting and promising strategy in drug designing. The hybrid compounds are formed by combing the two or more than two biologically potential active moieties. It is considered that the hybrids or conjugate compounds are more biologically active than any of the parent one and propose to work on the same biologically pathway. At present, there is no promising drug/ vaccine available in the market, therefore, it is very important to work on the finding of drug to cure the patients from the SARS-CoV-2 infection i.e. COVID-19. In this work, authors have used molecular docking and ADMET score to study the binding affinity of xanthene-triazole-chloroquinoline/ xanthenechloroquinoline hybrid analogues against main proteases of SARS-CoV-2 to assist drug discovery against coronavirus disease-19 (COVID-19). The compounds used in this paper for binding studies were taken from the previously published methods by our research group. Xanthene-triazole-quinoline based analogues i.e. 2-((1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)-12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-ones (AP1-AP15; Table 1 ) were synthesized by one pot threecomponent condensation of 12-aryl-2-hydroxytetrahydrob-enzo[a]xasnthene-11-ones, propargyl bromide and 4-azido-7-chloro-quinoline in the presence of K 2 CO 3 as a base and 10 mol% CuSO 4 .5H 2 O and 20 mol% sodium ascorbate in PEG-400 at 80°C (Scheme 1). While xanthene-chloroquinoline hybrid analogues i.e. 12-aryl-2-hydroxy-8,9,10,12tetrahydrobenzo[a]xanthene-11-ones (A1-A17; Table 2 Table 1 Derivatives of xanthene-triazolequinolines Table 2 Derivatives of xanthenechloroquinolines The protease of SARS-CoV-2 (PDB ID -6LU7) was prepared with the help of UCSF Chimera 1.11.2, so it can be used in the docking of compounds to study the interactions between the ligand and the receptor. Vijay, Kamlesh et al. 2020) Herein, removal of incomplete residues and solvents was done as well the hydrogen and charges were added by using the AMBER.ff14SB force field. The previously synthesized compounds were optimized to be used in the docking with the main protease of SARS-CoV-2 for the COVID-19. (Yang and Chen Molecular docking is an important study to find the interaction between the small Physiochemical properties of small molecule is very important to understand its applicability as a drug, therefore, drug likeness and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of the best six molecules were determined. These descriptors have significant or master role in deciding a molecule to act as drug. Molecular weight, heavy atoms, number of rotatable bonds, H-bond donors, H-bond acceptors, solubility (log S), distribution coefficient (log D 7.4 ) and partition coefficient (log P) were calculated using the web server (http://admet.scbdd.com/calcpre/index/). The compounds synthesized previously by our groups were docked with the main protease of SARS-CoV-2 and the binding energy is given in Table 3 . Compounds number AP3, AP10, AP9, AP8, A17 and A11 showed best binding with the protease of SARS-CoV-2 based on the binding energy. Then, the interaction of the best six compounds (AP3, AP10, AP9, AP8, A17 & A11) with the main protease of SARS-CoV-2 have been studied as in Table 4 and the docked poses are given in Figure 1 . Table 5 . Absorption properties of the best six candidates (AP3, AP10, AP9, AP8, A17 and A11) Further, absorption properties of the best six compounds in terms of Caco-2 permeability, permeability glycoprotein (P-gp) for inhibitor and substrate, human intestinal absorption and bioavailability (F20% & F30%) are determined as in Table 6 . Caco-2 cells are the constituent of colon carcinoma and have similar epithelium of intestine. Caco-2 permeability determines the rate of reflux of a molecule to cross the Caco-2 monolayer. To be good drug, it should have satisfactory permeability and the value of Caco-2 permeability should be more than the -5.15. All the six compounds have good permeability. All the compounds have satisfactory values for HIA and others. Distributional properties {plasma protein binding (PPB), volume distribution (VD) and blood brain barrier penetration (BBB)} of top six compounds AP3, AP10, AP9, AP8, A17 and A11 are given in Table 7 . All the best six compounds have acceptable PPB, VD and BBB. Metabolism is simply the break-down of a molecule in the liver of the humans using different enzymatic reactions. Metabolic properties for best six compounds are determined for different isozymes of cytochrome P450 as in Table 8 and found acceptable. A compound may be eliminated from the human body in its original or with some changes and it take place through different organs but through kidney and liver are considered acceptable. Water soluble molecules or drugs can be excreted with urine and aqueous insoluble molecules cannot be excreted from kidney. There is need to cleavage of the water soluble molecule or species so they can be excreted with urine. Excretion of a molecule can be understood with the half-life (t 1/2 ) and clearance rate (CL). The values for the best six compounds (AP3, AP10, AP9, AP8, A17 and A11) are given in Table 9 . All best six compounds (AP3, AP10, AP9, AP8, A17 and A11) have half-life less than 3h and considered to be acceptable. Further, the clearance rate of excretion values of the compounds has three ranges: high for more than 15; moderate for 5-1 and low for less than 5. All top-six compounds have low clearance rate. Toxicity is a very important property of a molecule to be a drug. Many molecules are withdrawn due to the high toxicity and therefore, it is important to study toxicity behavior of the molecule before moving ahead in drug development. To develop a molecule into a drug, it is necessary to maintain a balance between the toxicity, potency and pharmacokinetics of drug. Toxicity of the molecules can damage different organs of the humans and it is studied as cytotoxicity, hepatotoxicity, etc. Toxicity of the best six compounds for human Ether-à-go-go-Related Gene (hERG) blockers, human hepatotoxicity (H-HT), ames mutagenicity, skin sensitization, half maximal lethal dose (LD50), drug induced liver injury (DILI) and maximum recommended daily dose (FDAMDD) are studied and are found acceptable. The values are given in Table 10 . Herein, xanthene based hybrid compounds were taken, were synthesized by our group and they were studied to find their in inhibition of main protease of SARS-CoV-2 using different computations tools. Top six compounds were taken based on the binding affinity with the main protease of SARS-CoV-2 comes from the molecular docking. Then, the screened compounds studied for the ADMET properties to understand their potential to be like drug in future. 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M. Khurana for the guidance. The authors of the manuscript declare that they have no conflict of interest. Need of finding promising agents for the inhibition of main protease of SARS-CoV-2.  Previously synthesized xanthenes were used. ADMET properties were determined.