Investigation of potential inhibitors of Sars-CoV-2 main protease 3clpro by molecular docking and pharmacokinetic methods

On December 30, 2019, a new virus emerged in the city of Wuhan, Hubei province of China, and quickly spread to more than 150 countries [2]. As a result of the studies carried out by scientists on this new virus, it was concluded that the virus shares <80% nucleotide identity and 89.10% nucleotide [9] similarity with Sars Cov virus genes, and they occur despite sequence diversity[1]. On February 12, the World Health Organization (WHO) named this new virus as severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2) and the disease causing it as 2019 Coronavirus Disease (Covid-2019, Covid-19) [2] . Coronaviruses are spherical, large, single-stranded, positively sensitive, have an envelope on their surface [4] and have the largest genome size in the range of approximately 26-32 kilobases (kb) with the extensions they have on their surface and the genetic material (genome) they contain [3] Virus particles ranging in diameter from 60 to 140 nm [5]. Sars-CoV-2 is a non-segmented, 9860 amino acid encoding, 29.903 (~30.000) nucleotide-containing, enveloped [21], positive-sense, single-stranded, RNA viruses belonging to the B beta coronavirus genus, with extensions on their surface and a genome size of 28 kilobases (~30) with the genetic material they contain [1]. The genomic RNA (gRNA) of SARS-CoV-2 has 14 open reading frames (ORFs). The 2 main ORFs (ORF1a and ORF1b open reading circle) are translated into 2 viral replicase polyproteins (pp1a and pp1ab) via the (-1) ribosomal frameshift mechanism [21]. These 2 polyproteins make up two-thirds of the total genome [1], [23] ,[24]. These polyproteins are also processed by 2 important viral proteases (papain-like prosthesis(PL pro ) and 3 chymotrypsin-like proteases(3CL pro )) to form nonstructural protein(Nsps1-16)'s [1],[25]. If the activity of the 3-chymotrypsin-like protease enzyme is inhibited, the virus will become dysfunctional. For this reason, the 3-chymotrypsin-like protease (3CL pro ) is a good potential target. Despite intensive efforts by scientists, there is currently no specific drug for the treatment of sars cov 2 disease. Our aim is to analyze the active ingredients and various plants in drugs that are good for sars cov 2 disease as a result of in vitro, preclinical,clinical studies, using structure-based drug design methods (docking, virtual ligand screening) against a new epidemic that occurs suddenly, does not have a specific drug, and spreads rapidly from person to person. It is the search for candidate compounds that can be 3-chymotrypsin-like protease enzyme inhibitors by utilizing the phytochemicals in it. In the first phase of the study, validation of the AutoDock Vina program was performed for 7C6S. As a result of the calculation, the RMSD value was found to be 1.978 Å. Since this value is less than 2 Å, it was determined that this program is suitable for the selected system. In the second stage of the study,as a result of in vitro,preclinical,clinial studies, the binding of active ingredients in drugs (Lumacaftor, Aprepitant, conivaptan …etc) that are good for sars cov 2 disease and some phytochemicals (Hypericin, Theaflavine, Pseudohypericin, Amentoflavone, Agathisflavone …etc) in 8 plants (Hypericum Perforatum L, Anacardium Occidentale, Camellia Sinensis …v.s) to the active site of 3CL pro enzyme was carried out with the AutoDock Vina program. 2 active drug (Lumakaftor(-9.0 kcal/mol) ve Aprepitant(-8.9 kcal/mol)) substances and 4 phytochemicals (Hypericin(-9.4 kcal/mol), Theaflavine(-9.3 kcal/mol), Pseudohypericin(-9.2 kcal/mol), Amentoflavone(-9.2 kcal/mol)) in Hypericum perforatum L and Camellia sinensis plants show the best binding. In the third stage of the study, the compatibility of the biological activity(the degree of efficacy of any nutrient in an organism) assets and Lipinski rule for 19 plant phytochemicals was determined by the Molinspiration Cheminformatics Program. In the fourth stage of the study, Admet (absorption, distribution, metabolism, excretion and toxicity) analyzes were performed for 19 plant phytochemicals via AdmetSar 1.0 Program. At the last stage of the study, using the ZINC15 database, potential ligands were searched for virtual ligands based on the active ingredients of (Lumakaftor(-9.0 kcal/mol) ve Aprepitant(-8.9 kcal/mol)) and Hypericum perforatum L (Sarı Kantaron) (Hiperisin(-9.4 kcal/mol) herb. As a result of these calculations, it was found that the first 5 compounds with the best binding affinity could be promising candidate compounds for COVİD 19. The data obtained as a result of the studies in this thesis will contribute to the design of new candidate compounds that may be effective for 3-chymotrypsin-like protease.