After the Covid-19 pandemic and the aggressively infection control measures taken by the governments in the whole world, the need for a rapid pharmaceutical solution was more that necessary. The computer aided chemistry and molecular docking is a rapid tool to drug screening and investigation. Moreover, more metal based drugs are tested daily by research institutes for their antiviral activity. Here, we used theoretical studies on previously published biological active complex molecules of vanadium as an example of evaluating possible drug candidates before entering the laboratory. Our findings suggest that theoretical investigation should always precede on drug discovery.
Research Article
Screening Possible Drug Molecules for Covid-19. The Example of Vanadium (III/IV/V) Complex Molecules with Computational Chemistry and Molecular Docking.
https://doi.org/10.21203/rs.3.rs-34033/v1
This work is licensed under a CC BY 4.0 License
Journal Publication
published 30 Apr, 2021
Version 1
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Nowadays the scientific community faces a unique situation due to the Covid–19 disease. The World Health Organization (WHO), declared the coronavirus disease a global pandemic in March 2020 [1]. Generally speaking, Covid–19 is a member of Betacoronoviruses, the former human coronaviruses SARS and MERS [2].
SARS-CoV–2 belongs to the +RNA virus family that utilize single-stranded positive-sense RNA molecules as genomes. SARS-CoV–2, a positive strand RNA virus encodes four structural proteins the matrix (M), small envelope (E), spike (S) and nucleocapsid phosphoprotein (N). Moreover, sixteen non-structural proteins (nsp1–16), the nucleocapsid phosphoprotein N which is essential for linking the viral genome to the viral membrane and its N-terminal RNA binding domain (N-NTD) that captures the RNA genome [3].
The effective options of drug therapy and vaccination are currently under evaluation and our societies are trying to supress the disease with aggressively infection control measures [4]. Having in mind these facts we are underlying the need of a rapid evaluation of possible drug candidates. This will save money and time to the drug industry in order to shift the research in a clearer synthetic path. As far as now, very few studies, discussed bioinformatics [5] and computer aided techniques as a more efficient way to fight the Covid–19 pandemic disease. In addition, Shi et al. [6] developed a molecular docking web-based server to discover new drug targets, or active compounds. Yan et al. [7] conclude that a structure-based rational design of binders with enhanced affinities the S protein of the coronaviruses may facilitate development of decoy ligands or neutralizing antibodies for suppression of viral infection, and Lung et al. [8] suggested a potential SARS‐CoV‐2 RdRp inhibitor for further study using molecular docking studies. Molecular docking has several strengths, among which the method’s ability to screen large compound databases at low cost compared to experimental techniques [9,10] and Open source software development provides many advantages to users of modelling applications, not the least of which is that the software is free and completely extendable [11,12].
On the other hand, there is an increase interest in the development of metal-based drugs [13,14] and some of them exhibited interest activities against viruses [15,16]. Vanadium complexes are in use because of the low toxicity of vanadium metal in comparison with others such as platinum. Pharmaceuticals based on vanadium complexes have attracted the interest of scientists due to the biological activity of vanadium molecules, for example antidiabetic properties, and their low toxicity [17].
Herein, we describe the use of five vanadium (III/IV/V) complexes as potential candidates in drug screening with computer aided chemistry for Covid–19. In particular, we used the example of β-tocDEA (V5+) and β-tocDPA (V4+) as reported in [17], the binuclear V5+bdeah [18], and binuclear V3+bicah complex molecule [19].Finally based on the theoretical studies we designed for the first time the V5+Xn complex molecule, a vanadium complex with xanthohumol which is a prenylated chalcone. We performed molecular dynamics studies, DFT studies and molecular docking studies against BSA (transport protein), 6M03 (Covid–19 main protease), 6M71 (SARS-COV–2 RNA-dependent polymerase) and 6YI3 the N-terminal RNA-binding domain of the SARS-CoV–2 nucleocapsid phosphoprotein.
2.1 Materials
To create 2D and 3D structures of the ligand molecules, Chem3d Pro 12.0 and AVOGADRO 1.90.0 software programmes were used. Ligand optimisations were done by ORCA 4.1.1 software while ligands and receptor preparation studies were done by Chimera 1.14. Molecular docking studies were carried out by Autodock 4.2 and docking results were analysed by Chimera 1.14 program. Additionally, calculations on docking studies performed using iGEMDOCK 2.1 software. BSA, 6M03, 6M71 and 6YI3 coded crystal structures were selected from Protein Data Bank (www.rcsb.org). Ligand molecules were collected by literature [17–19].
2.2 Methods
2.2.1 Computational Chemistry
Geometric optimization calculations were performed in accordance with DFT method [20]. Frequency calculations were performed to obtain thermodynamic properties and to verify that each optimization achieved an energy minimum. The quantum chemical descriptors extracted directly from the ORCA output file were Huckel charge, electronic density, dipole moment, the energy of the highest occupied molecular orbital (HOMO), and the energy of the lowest unoccupied molecular orbital (LUMO) [21,22].
2.2.2 Receptor Preparation
All water molecules were removed, hydrogen atoms were added, the end residues were repaired, and energy minimization was performed on the protein. Docking calculations were performed through Autodock generation using the ligand, the protein was fixed while the ligand was flexible, and the default parameters were used as described [23].
2.2.3 Docking Studies
Docking studies were performed with a number of 150 individuals in population, maximum energy evaluations of 2,500,000, and maximum generation of 54,000 to result in 100 docking poses [24].
3.1 Theoretical Chemistry
The optimized structures of the studied complex molecules are depicted in Fig.1a. The DFT results are within the same range as MP2. For Vbicah and Vbdea we can say that the theoretical studies agreed with the experimentally x-ray structures from the literature. The structures of xanthohumol molecule and complexed with vanadium structure of the molecule can be found in Fig.1b. The Huckel charges and the calculated molecular geometry parameters can be found in Tables A1, A2 and B respectively in the supplementary material. Calculated geometry parameters for Vbicah and Vbdeah are in conformity with experimental ones [18,19]. It is widely known that DFT calculation results strongly depend on used functionals and to some extend on used solvents in model [25]. The molecular electrostatic potential and the solvent accessibility of all the molecules studied in this paper are shown in Fig.2a and Fig.2b. These were in good correlation with Huckel charges values.
As can be seen from Table 1. the calculated total energies of Vtocdea, Vtocdpa and VXn are in order from lowest to highest Vtocdea The value of the energy difference between HOMO and LUMO as well as the highest occupied molecular orbital (EHOMO) and lowest unoccupied molecular orbital (ELUMO) energies plays a very important role in stability and reactivity of molecules. The EHOMO energies of molecules show the molecule’s ability to give electrons. On the other hand, ELUMO characterizes the ability of the compound to accept electrons. The energy gap of Vtocdea and Vtocdpa is similar, a fact that it is corelated with the experimental values [17], showing that the vanadium ion in Vtocdea is in oxidation state +5 while in Vtocdpa the vanadium ion is in oxidation state +4.
The electronic correlation effects play an essential role in the stability of these type of systems, and therefore, it will affect the equilibrium distances and the interaction energies.
Electronegativity (χ) is a measure of the power of an atom to attract a bonding pair of electrons. According to this theorem is expressed as follows. Based on equation (1) larger Δgap always indicates lower chemical reactivity and higher kinetic stability of the investigated species. The chemical reactivity of molecules is caused by the simultaneous effect of different parameters. The distribution and energy of HOMO is an important parameter to explain the antioxidant potential of phenolic antioxidants. The electron-donating capacity of the molecule can be predicted by looking at the energy values of HOMO. The value of the energy difference between HOMO and LUMO as well as the highest occupied molecular orbital (EHOMO) and lowest unoccupied molecular orbital (ELUMO) energies plays a very important role in stability and reactivity [24]. Table 1. Calculated minimised energies for complex molecules of Vanadium with natural phenolic ligands Calculated Values Vtocdea Vtocdpa VXn Stretch 32.54 81.37 45.28 Bend 84.91 215.51 182.24 Stretch-Bend 1.27 -14.20 0.26 Torsion 18.15 22.38 -1.47 Non-1.4 VDW -19.89 -23.76 -0.87 1.4 VDW 36.08 37.86 20.33 Dipole-Dipole 2.15 ------- 0.65 Total Energy 156.2 Kcal/mol 354.79 Kcal/mol 246.43 Kcal/mol As we can see in Table 2. Vtocdea and Vtocdpa have similar reactivities and kinetic stability. The same is expected for VXn which is a complex molecule designed based on these two. Based on these results we have used the geometry of the model Tocopherol to design VXanthohumol (both are vanadium complexes with natural ligands) and the results confirmed that. Table 2. Quantum chemical parameters for studied molecules Complex Molecule Metal Ion HOMO LUMO Δgap Vbicah V(10) V3+ -13.043 0.526 13.569 Vbicah V(23) V3+ -15.036 36.811 51.847 Vbdea V(16) V5+ -14.557 32.555 47.112 Vbdea V(21) V5+ -15.298 36.063 51.361 Vtocdea V5+ -20.056 41.397 61.453 Vtocdpa V4+ -20.292 41.825 62.117 VXn V4+ -18.801 43.473 62.274 Molecular docking method is one of the frequently referred structure-based design methods [28,29]. We decided that because the ligand molecules would be screened as a drug candidate for Covid-19, to perform studies with several related proteins to Covid-19 as we discussed in introduction, and at least with one plasma transport protein. In Fig 4. We can see the crystal structures that we used for molecular docking studies. The Vtocdea molecule interaction with 6YI3 is depicted in Fig 5. while, if Fig 6. we can se the relatively position of Vtocdea and VXn molecules on 6M03 and 6M71 respectively. Moreover, the hydrogen bonding interactions of amino acid residue of structure 6M71 with Vtocdpa molecule, are shown in Fig 7. Docking analyses showed that VXn coded ligand has the best binding score among all ligands with BSA protein, followed by Xn with a binding free energy of −108.72 kcal/mol. It makes hydrogen bonds with ASP108, PRO146, TYR147 and ILE455 (four H bonds), and also interacts with BSA with Van der Waals forces with a binding free energy of −93.23 kcal/mol. Regarding the N-terminal RNA-binding domain of the SARS-CoV-2 nucleocapsid phosphoprotein (6YI3) the molecule Vbicah has a binding free energy of -108.88 kcal/mol, followed by VXn with -105.23 kcal/mol. In fig. 8 we are seeing the percentage interaction energies of the amino acid’s residue of 6YI3 on the studied molecules. In particular, the highest energy interaction of Xn molecule with 6YI3 is related with the amino acid glutamine, while for VXn the highest energy related interaction with the same protein comes from the amino acid arginine. Interestingly both Vbdeah and Vbicah interact more with the amino acid asparagine of the 6YI3. Continuing with SARS-COV-2 RNA-dependent polymerase (6M71) starting with the ligand molecule with the highest affinity to the protein, Vbicah is the first with -102.66 kcal/mol followed by Vtocdea -98.91 Kcal/mol, Vtocdpa -97.06 Kcal/mol, Xn -96.03 Kcal/mol, VXn -93.64 Kcal/mol and finally Vbdea with -86.47 Kcal/mol. Finally, for Covid-19 main protease (6M03), Vtocdea and VXn are amongst the highest molecules in terms of binding affinity with the specific protein. Vtocdea interacts through hydrogen bonds with SER255 and PRO322 (2 H bonds) whereas, VXn interacts through hydrogen bonds with the amino acids GLN110 and THR111. All the detailed information about the energy amounts of the ligand molecules through the different proteins and the hydrophobic interactions of the amino acids with these molecules can be found in Table 3.
3.2 Molecular Docking
Table 3. ΔGbind energies and amino acid residues of the molecules interacting with BSA, 6YI3, 6M71 and 6M03.
|
Complex (Protein-Ligand) |
ΔGbind (Kcal/mol) |
Van der Waals |
Hydrogen Bond |
Electrostatic Forces |
Amino acids that interact through hydrogen bonds |
Amino acids that make hydrophobic interactions |
|
Vbicah-BSA |
-85.81 |
-71.51 |
-14.3 |
0 |
LEU304, HIS304 |
LEU301, PRO302, PRO303(M*), PRO303(S*), LEU304, TYR333, ARG336, HIS337, PHE373 |
|
Vbicah-6YI3 |
-108.88 |
-79.63 |
-29.25 |
0 |
ASP23, LYS25, ASN86, GLY89, TRP92 |
ASP23, ASN86(M), ASN86(S), ASP88, ILE90, TRP92 |
|
Vbicah-6M71 |
-102.66 |
-65.5 |
-37.16 |
0 |
TYR129, HIS133, SER709, THR710, ASP711, LYS714, ASN781 |
TYR32, TYR129, SER709, LYS780, ASN781 |
|
Vbicah-6M03 |
-106.62 |
-47.26 |
-59.37 |
0 |
HIS41, SER46, LEU141, ASN142, GLY143, SER144(M), SER144(S), CYS145(M), CYS145(S), HIS163, GLU166 |
HIS41, MET49, ASN142(M), ASN142(S), HIS163, GLU166 |
|
Vbdea-BSA |
-85.66 |
-57.44 |
-28.22 |
0 |
HIS145, SER192, SER428, ARG458 |
LEU189, SER192, ARG196 |
|
Vbdea-6YI3 |
-86.78 |
-66.63 |
-20.15 |
0 |
ASP23, LYS25, GLY89, ILE90 |
ASN86(M), ASN86(S), ASP88, ILE91, TRP92 |
|
Vbdea-6M71 |
-86.47 |
-65.28 |
-21.19 |
0 |
LYS47, ASN138, ASP140, THR141(M), THR141(S), LEU142 |
TYR32, LYS47, ALA130, ASP140, THR141 |
|
Vbdea-6M03 |
-87.35 |
-71.16 |
-16.18 |
0 |
GLY143, SER144(M), SER144(S), CYS145, HIS163 |
HIS41, SER46, MET49, LEU141, ASN142, MET165, GLN189 |
|
Vtocdea-BSA |
-85.52 |
-81.6 |
-3.5 |
-0.42 |
ASN161 |
ASP129, GLU130(M), GLU130(S), LYS131(M), LYS131(S), TRP134, ASN158, ASN161 |
|
Vtocdea-6YI3 |
-78.58 |
-78.58 |
0 |
0 |
------- |
THR14, ALA116, ILE117, VAL118, GLN120, GLU134, GLY135 |
|
Vtocdea-6M71 |
-98.91 |
-93.41 |
-5.5 |
0 |
SER255, PRO322 |
TYR265, LYS267, TRP268(M), TRP268(S), ASP269(M), ASP269(S), LEU270, PRO322(M), PRO322(S) |
|
Vtocdea-6M03 |
-86.01 |
-76.32 |
-9.98 |
0.29 |
GLN110, ASN203 |
GLY109, GLN110, VAL202, ASN203, GLU240, PRO241, HIS246, ILE249 |
|
Vtocdpa-BSA |
-99.14 |
-94.43 |
-6.33 |
1.62 |
ARG144 |
ASP111, LEU112, PRO113, LYS114(M), LYS114(S), LEU115(M), LEU115(S), ARG144, ARG185, GLU424, ILE522 |
|
Vtocdpa-6YI3 |
-96.79 |
-93.29 |
-3.5 |
0 |
LEU149 |
HIS19, LEU121, THR126(M), THR126(S), LEU127(M), LEU127(S), PRO128, LYS129, GLY130, PHE131, TYR132 |
|
Vtocdpa-6M71 |
-97.06 |
-89.12 |
-5 |
-2.94 |
ASP761 |
HIS439, SER549, ARG555, TRP617, GLU811, CYS813, SER814, ARG836 |
|
Vtocdpa-6M03 |
-87.24 |
-84.32 |
-2.74 |
-0.18 |
HIS246 |
GLN107, PRO108, GLY109, VAL202, GLU240, HIS246 |
|
VXn-BSA |
-108.72 |
-93.23 |
-15.5 |
0 |
ASP108, PRO146, TYR147, ILE455 |
HIS145(M), HIS145(S), LEU189(M), LEU189(S), SER192, ALA193(M), ALA193(S), ARG196, ARG458 |
|
VXn-6YI3 |
-105.23 |
-74.36 |
-30.87 |
0 |
PHE26, ARG28, TYR83, TRP92, THR95 |
ARG28(M), ARG28(S), TYR83, TRP92, VAL93(M), VAL93(S) |
|
VXn-6M71 |
-93.64 |
-80.61 |
-13.03 |
0 |
ARG29, THR252 |
THR246, LEU247, ARG249, THR319, LEU460, PRO461 |
|
VXn-6M03 |
-91.83 |
-79.41 |
-12.42 |
0 |
GLN110, THR111 |
GLY109, GLN110(M), GLN110(S), THR292, PHE294 |
|
Xn-BSA |
-103.32 |
-94.04 |
-9.28 |
0 |
ARG458 |
ASP108, HIS145, LEU189(M), LEU189(S), SER192(M), SER192(S), ALA193, ARG196, ARG458 |
|
Xn-6YI3 |
-87.4 |
-70.41 |
-17 |
0 |
PRO122, GLN123(M), GLN123(S), GLY124 |
GLN120, LEU121, PRO122, GLN123(M), GLN123(S), GLY124, THR126 |
|
Xn-6M71 |
-96.03 |
-74.54 |
-21.49 |
0 |
LYS621(M), LYS621(S), ARG624 |
ARG553, ASP618, TYR619, PRO620, LYS621, ASP623, ARG624, ASP760 |
|
Xn-6M03 |
-80.46 |
-62.77 |
-17.7 |
0 |
ASP33, ASP34, SER81(M), SER81(S), LYS88 |
ASP33, VAL35, LYS88, LEU89, LYS90(M), LYS90(S), TYR101 |
*M stands for main chain of the protein whereas S stands for the side chain of the protein
The presence of the electrostatic forces on those interactions was limited. Electrostatic interactions can only be seen on the interaction between Vtocdea with BSA (-0.42 Kcal/mol), Vtocdea with 6M03 (0.29 Kcal/mol), Vtocdpa with BSA (1.62 Kcal/mol), Vtocdpa with 6M71 (-2.94 Kcal/mol) and Vtocdpa with 6M03 (-0.18 Kcal/mol). The electrostatic interactions of Vtocdea and Vtocdpa are in correlation with literature [17], indicating that these molecules are having anticancer activity through the disruptions of electron transfer cycle in mitochondria. Having in mind the theoretical studies we suggest that molecules such as Vtocdea and VXn are good candidates to tested in vitro and in vivo, against the Covid-19 disease.
In this study we performed several theoretical studies on vanadium complexes with biological activity from the literature. Based on that, we designed a new one the VXn molecule that showed similar activity with Vtocdea. We used computational chemistry methods to take valuable information of the molecules and performed molecular docking studies on Covid-19 related structures. Knowing from literature that Vtocdea exhibits the highest biological activity having at the same time the least toxicity in healthy cells, we conclude that these techniques should be used by the scientific community to save time and money on the fight against Covid-19 and take these valuable information in order to discover novel drug therapies with high effectiveness and the least toxicity.
Disclosure statement
No potential conflict of interest was reported by the authors.
ORCID
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