key: cord-0914192-g4yhx100 authors: Aitouna, A. Ouled; Belghiti, ME.; Eşme, Aslı; Anouar, El Hassane; Aitouna, A. Ouled; Zeroual, A; Salah, M.; Chakroun, A.; Abdallaoui, H. El Alaoui El; Benharref, A.; Mazoir, N. title: Chemical Reactivities and Molecular Docking Studies of Parthenolide with the main protease of HEP-G2 and SARS-CoV-2 date: 2021-05-19 journal: J Mol Struct DOI: 10.1016/j.molstruc.2021.130705 sha: 3863c273ba0bd6e95ec4d7c480ae3b6c33b401ac doc_id: 914192 cord_uid: g4yhx100 We have used bioinformatics to identify drugs for the treatment of COVID-19, using drugs already being tested for the treatment as benchmarks like Remdesivir and Chloroquine. Our findings provide further support for drugs that are already being explored as therapeutic agents for the treatment of COVID-19 and identify promising new targets that merit further investigation. In addition, the epoxidation of Parthenolide 1 using peracids, has been scrutinized within the MEDT at the B3LYP/6-311(d,p) computational level. DFT results showed a high chemoselectivity on the double bond C(3)=C(4), in full agreement with the experimental outcomes. ELF analysis demonstrated that epoxidation reaction took place through a one-step mechanism, in which the formation of the two new C-O single bonds is somewhat asynchronous. Epoxidation is a reaction of both industrial and academic importance [1] . The formed epoxides [2] [3] [4] [5] [6] represent an extremely useful intermediate which could be converted to higher value chemical compounds [7] . Moreover, epoxides are present in a large range of natural products [8, 9] and biologically active compounds [10] [11] [12] [13] . Epoxides can be accessed in numerous ways, but the most common method consist the epoxidation of olefins using peracids [14] . Peracids are widely used for the epoxidation of olefins; owing to their high reactivity permit them to be used under relatively mild reaction conditions without using any catalyst, the m-CPBA being the most widely used in epoxidation (Scheme 1). The interest for the use of oxidizing agents which are safe for the environment keeps increasing. Indeed, hydrogen peroxide (H 2 O 2 ) is a very interesting alternative since its secondary decomposition products are water and oxygen. It is less expensive and more accessible than some of the traditional oxidizing agents. Consequently, from both ecological and economical decision, it is enviable to utilize a catalytic epoxidation employing aqueous hydrogen peroxide as oxidant, and transition metal complexe as catalysis. The substrate employed such as transition metal complexes became very attractive technologies and environmentally friendly asymmetric epoxidation. The current reports have described several remarkable catalytic systems in the presence of hydrogen peroxide such as iron [15] , tungsten [16] , vanadium [17, 18] , Manganese [19] [20] [21] , bicarbonate [22, 23] and dioxolane [24] .Various theories have been developed to elucidate the molecular mechanism, reactivity and selectivities (regio, chemo and stereo). The bonding evolution theory (BET) [25] , the conceptual density functional theory (CDFT) [26] , and the electron localization function (ELF) method [27] , have presented to scrutinize the reaction mechanism [28] within a current model named a molecular electron density theory (MEDT) [29] . Our theoretical studies devoted to the epoxidation of R-carvone with peracid demonstrate a high chemoselectivity involving the C=C double bond carrying the methyl group and the low diastereoselectivity [30] . The many medicinal properties of parthenolides products we have tried to investigate about its efficiency against cancer and SARS-CoV-2 by docking protocol, seen that the novo development of antivirals in vitro need a very long time-, expensive cost-, and effort-intensive endeavor. New double mutant variant discovered in India continues to spread around the world, with specialists more than once stressing the importance of changing our way of life in order to stay safe [31] [32] [33] [34] . Thus, in this moment, it is important to generate specific antivirals especially for SARS-CoV-2 [35] [36] [37] [38] in very short time by testing potential medicinal compounds in silico, seen the increasing structural data of key proteins [39, 40] . Molecular docking provides a powerful tool in understanding the degree of recognition between the tested compounds and the amino acids of the enzyme active site. Throughout the virtual screening, the ligand molecules were flexible and macromolecule was kept as rigid [33] . In this context, we have examined influence of parthenolides products (4-7) against Coronavirus (Covid-19) using Docking tools and we have also studied the stereoisomerism DFT computations were executed employing the B3LYP functional [42, 43] jointly with the 6-311G(d,p) basis set [44] . Optimizations were supported out utilising the Berny analytical gradient optimization technique [45, 46] . The stationary points were described by frequency calculations so as to confirm that TSs have only one imaginary frequency. The intrinsic reaction coordinates [47] (IRC) paths were drawn to pattern the energy profiles joining every TS to the two related minima [48, 49] . The impact of dichloromethane (DCM) as solvent was considered by full improvement of the gas stage structures utilizing the polarisable continuum model (PCM) developed by Tomasi's group [50] [51] [52] [53] . Conceptual DFT (CDFT) global reactivity indices [54] and Parr functions were calculated exploiting the equations contributed in reference [55] . Each calculation was carried out with the Gaussian 09 [56] . Topological analyses of the ELF were functioned with the TopMod package using the monodeterminantal wave functions [57]. Numerous studies devoted to organic reactions have shown that the examination of the reactivity indices defined within CDFT [58] is a powerful tool to understand organic chemical reactivity. Thus, in order to predict the reactivity of parthenolide 1 in epoxidation reaction, the global indices gathered in Table 1 , i.e. the electronic chemical potential, μ, chemical hardness, η, electrophilicity, ω, and nucleophilicity, N, are analyzed. The electrophilicity ω indices of the alkene 1 and 1.53 eV whereas the nucleophilicity N indices are 3.22eV, respectively, these values allow classifying alkene 1 as strong electrophiles and strong nucleophiles within the electrophilicity and the nucleophilicity scales [59] . The electrophilicity ω indices of the oxidants EPA and m-CPBA are 1.08 and 1.76 eV, while the nucleophilicity N indices are 1.83 and 2.45eV, respectively. Thus, the oxidant EPA is classified as a moderate electrophile and a marginal nucleophile, while m-CPBA is classified as a strong electrophile and a moderate nucleophile. In this epoxidation the alkene 1 will participates as nucleophiles and the oxidants EPA and m-CPBA as electrophiles. In recent times, the electrophilic + and nucleophilic − Parr functions have been proposed to examine the local reactivity involving reactions between a nucleophile/electrophile pair [60, 61] . Therefore, the nucleophilic − Parr functions for parthenolide 1 are analyzed ( Figure 2 ). Owed to the non-symmetry of parthenolide 1 and peracids (2 and 3), two competitive reaction channels are feasible for the reaction between them. There are related to the two regioisomeric approach modes of the parthenolide relative to the double bond C 3 =C 4 and double bond C 1 =C 2 . The investigation of the stationary points elaborates in the epoxidation of parthenolide 1 and peracids 2 and 3 shows that these reactions follow a one-step mechanism. Therefore, the reactions between parthenolide 1 and peracid followed by the two TSs for each peracid represented by TS-1, TS-2, TS-3, and TS-4 and their corresponding epoxides, Relative energies are arranged in Scheme 3 and complete energies data are showed in Tables S1. The Gibbs free energies profiles of the reaction paths associated with the epoxidation reaction of parthenolide 1 and peracid are presented in Figure 3 , while the complete thermodynamic data are given in Table S2 in Supplementary Material. The Gibbs free energies profiles of the reaction paths associated with the epoxidation of parthenolide 1 by m-CPBA and CH 3 CO 3 H are presented in Figure 3 . According to transition state theory (TST), the second order rate constant (k TST ) at a given temperature (T) can be determined using the following equation [62, 63] : Where k B , h, C 0 , and R denote Boltzmann's constant, Planck's constant, standard concentration (1mol l -1 ), and the universal gas constant R = 1,987 cal·K -1 ·mol -1 , respectively. It is considered that K TST (ETPA), the rate constant of the epoxidation reaction of parthenolide 1 by CH 3 CO 3 H and K TST (m-CPBA), the rate constant epoxidation reaction of 1 using m-CPBA: This result indicates that the epoxidation reaction rate using ETPA is greater than the epoxidation rate by m-CPBA, which shows that the use of CH 3 CO 3 H is more effective than m-CPBA and also an environmentally friendly oxidant for which ethanoic (or acetic) acid is the sole byproduct. The most effective interaction between oxygen (O) and hydrogen (H) atoms can be seen as red areas in the Hirshfeld surface (HS) analysis, which provides a convenient analysis of intermolecular interactions within a crystal. The Hirshfeld surface is mapped using the normalized contact distance d norm , defined in terms of d i and d e distances, which represent the distance from the Hirshfeld surface to the nearest nucleus inside and external the surface, respectively. All the Hirshfeld surfaces (d norm , shape index, curvedness, and the related twodimensional (2D) finger print plots) were performed by using the Crystal Explorer 3.1 [54] . H…H (48.3%) contacts summarized in the two-dimensional (2-D) fingerprint plot make the largest contribution to the Hirshfeld surfaces. As seen in figure 6 . Hirshfeld, the O…H (44.1%) interactions occur as two distinct spikes in the upper right area of the 2-D fingerprint plots. The characteristic shape of C…H is similar to 'wings' as shown in figure 6 . Hirshfeld and the percentage contribution of this contact is 7.0% for the studied compound. The parthenolide molecule and several structurally related analogs have recently been attributed to having anticancer properties [65, 66] . Present study provides the influence of the stereoselectivity on anticancer activity for the parent parthenolides (9α-hydroxyparthenolide 2 and 9β-hydroxyparthenolide 3). Molecular docking study was carried out to identify the potential binding affinities and the mode of interaction of the two parthenolides 2 and 3 against the HEP- Table 2 . Discovery Studio Visualizer software was used to analyze the output of docking process [68] . The 2D and 3D molecular surface maps of the most active compounds Parthenolide 2 and Parthenolide 3 docking into the 3GCW binding sites is shown in Figure 7 . To test Parthenolide 4-Parthenolide 7, Remdesivir and Chloroquine compounds as probable targeted therapeutic agents of SARS-CoV-2, their molecular docking into the active site of the main protease (M pro ) of SARS-CoV-2: M pro is investigated. The intermolecular interactions between of the tilted compounds and the active residues of main protease have been explored using Auto dock package [67] . The staring geometries of main protease and the original docked ligand N3 were download from the RCSB data bank web site (PDB code 6LU7) [69] . The redocking of the original ligand into the active site of main protease is relatively well reproduced with a RMSD value of 2 Å. Stepwise of molecular docking study is reported in our previous study [70] . The binding affinity of Parthenolide4-Parthenolide 7, Remdesivir and Chloroquine compounds to active site of the main protease may strongly depend on the structural geometry of its basic skeletons, and the presence of specific substituted groups and heteroatoms ( Figure 8 ). In an attempt to determine the role of these parameters, molecular docking study has been carried out to determine their binding modes of Parthenolide 4-Parthenolide 7, Remdesivir and Chloroquine with main protease. Table 3 summarized the calculated binding energies of the stable complexes ligand-M Pro , number of conventional intermolecular hydrogen bonding established between the docked compounds and the active site residues of main protease. All the complexes formed between Parthenolide 4, Parthenolide 7, Remdesivir and Chloroquine compounds and the active residues of main protease display negative bending energies (Table 3) The molecular docking results revealed that Remdesivir has better binding affinity with (-7.99 kcal/mol) than Chloroquine (-6.91 kcal/mol). Remdesivir have more a number of residues closer to the ligand anchored in the active site than Chloroquine, showing that Remdesivir is a potent therapeutic inhibitor against 2019-nCoV than chloroquine. We performed molecular docking to assess whether or not it binds to the target with a high affinity for the SARS-CoV-2 protein. According to our results, we noticed that the Parthenolide 5 binds with high affinity to the selected target of the viral protein. We suggest that this compound could be a potential drug for SARS-CoV-2. The Parthenolide 5 compound required further cell validation and could be a hope for the development of anti-SARS-CoV-2 therapy. We also performed molecular docking to study parthenolide 2 and parthenolide 3 against the human liver cancer cell line HEP-G2, our results show that parthenolide 2 has the ability to form a conventional hydrogen bond which has a great importance in the stability of the protein-ligand complex with better binding affinity than standard drugs. The epoxidation reaction of parthenolide 1 has been investigated using DFT through density functional theory calculations at B3LYP/6-311G (d,p) computation level. The chemoisomeric reaction pathways associated with this epoxidation have been characterized and explored. Analysis of the CDFT indices accounts for the reactivity of parthenolide 1 was classified as a strong nucleophile and a marginal electrophile. Analysis of the nucleophilic − Parr functions indicated that the endocyclic (C 3 =C 4 ) double bond of parthenolide 1 is more nucleophilic than exocyclic double bond (C 1 =C 1 ). This characteristic explicated for the chemoselectivity and asynchronicity attained in the C-O bond creation at the most favourable TSs associated with the epoxidation reaction, in addition, analysis of the Gibbs free energy profiles demonstrated that this reaction presented a high chemoselectivity. This epoxidation was taken place through a onestep mechanism, in which the formation of the two new CO single bonds was somewhat asynchronous. 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