Abstract
Ripretinib is a recently developed drug for the treatment of adults with advanced gastrointestinal stromal tumors. This paper reports an attempt to study this molecule by electronic modeling and molecular mechanics to determine its composition and other specific chemical features via the density-functional theory (DFT), thereby affording sufficient information on the electronic properties and descriptors that can enable the estimation of its molecular bioactivity. We explored most of the physico-chemical properties of the molecule, as well as its stabilization, via the studies of the natural bond orbitals and noncovalent interactions. The electronic excitation, which is a time-dependent process, was examined by the time-dependent DFT with a CAM-B3LYP functional. The molecular docking study indicated that Ripretinib strongly docks with three known novel severe acute respiratory syndrome coronavirus 2 (SARS-n-CoV-2) proteins with a reasonably good docking score.
Keywords: Ripretinib, Density-functional theory, Time-dependent density-functional theory, Severe acute respiratory novel coronavirus 2, Molecular docking
1. Introduction
Gastrointestinal (GI) stromal tumors (GIST) are rare cancers that are associated with the possible metastatic invasion of other body parts, such as lungs, bones, and bone marrow [1]. They are due to the aberrant signaling of the proto-oncogene c-KIT [2,3]. GIST originates from cells that are known as the interstitial cells inside the wall of the GI tract. The interstitial cells are referred to as the GI tract “pacemaker cells” because they are the muscles that contract to push food and liquid along the GI tract. Imatinib, a cancer growth inhibitor called a tyrosine kinase inhibitor, along with the surgical removal of tumors is a gold standard treatment procedure for GIST [4]. Mahadevan demonstrated the resistance to imatinib while applying it to the treatment of cancer and proposed a TK switch to explain the drug resistance [4]. Ripretinib, another kinase inhibitor for treating advanced GIST, was recently developed as an efficient drug to inhibit the entire mutant KIT and PDGFRA kinases that are present in cancers and myeloproliferative neoplasms especially in drug-resistant cases [5]. Employing the structural drug design approach, Flynn and coworkers developed an inhibitor that could bind to the key amino acid residues via the KIT switching mechanism, and it was approved by FDA [6,7] and followed by intense clinical trials [8,9].
Severe acute respiratory syndrome (SARS), which is due to the novel coronavirus 2 (n-CoV-2) (SARS-n-CoV-2) has now emerged to the level of a pandemic that has impacted the lifestyle and health of most people globally [10]. Scientists worldwide are tirelessly working to establish the pathology [11] and epidemiology [11] to develop drugs and vaccines [12]. Chloroquine has been highlighted as a wonder drug for managing the coronavirus disease (COVID) despite the existing differences in opinions [13]. Remdesivir is now presently utilized widely to treat COVID-associated pneumonia [14]. The lopinavir, umifenovir, favipiravir, and oseltamivir molecules are also being studied as potentially active drugs against the virus [15]. Moreover, we have already reported that melatonin is active against this deadly virus [16] along with tucatinib [17] and selpercatinib [18]. Owing to the extensive time that is required to design and develop a drug to treat the virus, it is reasonable to reroute the existing drugs as molecular targets against the virus. Therefore, we considered rimegepant as a potential candidate in this study.
Here, we studied the structural and electronic features of the drug molecule, ripretinib. We employed the density-functional theory (DFT) to study its geometry and electronic and reactivity descriptors. Further, we evaluated the intramolecular electron delocalizations, noncovalent interactions (NCIs), and average local ionization energy indices of the molecule. The most beneficial finding of the study is the potential reuse of the drug as a supplement for the management of SARS-n-CoV-19. The molecular docking of the compound was performed with three known COVID proteins.
2. Methods
The antitumor drug, ripretinib, was optimized by the Gaussian-09 [19] software employing DFT [20] with B3LYP functional [[21], [22], [23]] and a 6-311G + (2 d,p) [24] basis set. We calculated the frequency to ensure that there was no imaginary frequency, thus ensuring that the obtained geometry corresponds to a global minimum for obtaining an optimized geometry. We employed the same geometry to calculate the frontier molecular orbital (FMO), the natural bonding orbitals (NBOs) and to generate the wave function files (.wfn files). To simulate the ultraviolet–visible (UV–Vis) spectrum, we employed the time-dependent DFT (TD-DFT) method [25] with long-range corrected CAM-B3LYP [26,27] functional and 6-311G + (2d,p) as a basis set since the electronic transitions were time-dependent phenomena in a methanol solvent and an Integral Equation Formalism Polarizable Continuum Model (IEFPCM) implicit solvation atmosphere [28,29]. GaussSum was employed to analyze the excited-state electronic transitions and electronic spectra [30]. The ripretinib molecule possesses more than two reaction sites, e.g., the phenylamide, 4-bromo-2-fluorophenyl, methanone, ethyl, methyl, and naphthyridin groups. The reaction sites of ripretinib were calculated by the Multiwavefunction suite employing the generated wfn file [31]. The other energy and reactivity descriptors, including the total electrostatic potential V(r) [23], average localized ionization energy (ALIE), hardness, and softness [32], were determined by the qualitative study of the different NCIs [32]. PDB IDs of the suitable proteins to assess the anti-CoV-2 biological activity of the ripretinib molecule were downloaded from the RCSB [33] site. The energy was obtained from SwissDock, and the score values were obtained from PatchDock [34]. Furthermore, the docked results were obtained from the Bio-discovery studio.
3. Results
3.1. Optimized geometry of ripretinib
The molecular structure of ripretinib was optimized by DFT, and DFT-B3LYP was employed for the structural confirmation with 6-311G + (2d,p) as the basis set. The optimized structure is shown in Fig. 1 and the details of its geometry are presented in Table 1 .
Fig. 1.
Optimized structure of ripretinib obtained by DFT (B3LYP/6-311G + (2d,p)) exhibiting the unique structure of the compound with two different halogens in the central ring.
Table 1.
Important structural parameters of the molecule (distances and angles).
| Name | Definition | Value (in Å) | Name | Definition | Value (in 0) |
|---|---|---|---|---|---|
| R1 | R(1Br—22C) | 1.94 | A1 | A(10C-5 N-13C) | 123.31 |
| R2 | R(2F—25C) | 1.40 | A2 | A(10C-5 N-14C) | 120.88 |
| R3 | R(3O—13C) | 1.25 | A3 | A(13C-5 N-14C) | 115.81 |
| R4 | R(4O—27C) | 1.25 | A4 | A(18C-6 N-19C) | 117.59 |
| R5 | R(5 N-10C) | 1.39 | A5 | A(19C-7 N-26C) | 122.92 |
| R6 | R(5 N-13C) | 1.42 | A6 | A(19C-7 N-44H) | 118.48 |
| R7 | R(5 N-14C) | 1.48 | A7 | A(26C-7 N-44H) | 118.61 |
| R8 | R(6 N-18C) | 1.34 | A8 | A(23C-8 N-27C) | 126.94 |
| R9 | R(6 N-19C) | 1.37 | A9 | A(23C-8 N-45H) | 113.80 |
| R10 | R(7 N-19C) | 1.37 | A10 | A(27C-8 N-45H) | 119.26 |
| R11 | R(7 N-26C) | 1.46 | A11 | A(27C-9 N-28C) | 128.01 |
| R12 | R(7 N-44H) | 1.01 | A12 | A(27-9 N-49H) | 117.57 |
| R13 | R(8 N-23C) | 1.41 | A13 | A(28C-9 N-49H) | 114.42 |
| R14 | R(8 N-27C) | 1.39 | A14 | A(5 N-10C-12C) | 118.39 |
| R15 | R(8 N-45H) | 1.01 | A15 | A(5 N-10C-17C) | 123.23 |
| R16 | R(9 N-27C) | 1.39 | A16 | A(12C-10C-17C) | 118.39 |
| R17 | R(9 N-28C) | 1.42 | A17 | A(13C-11C-15C) | 120.09 |
| R18 | R(9 N-49H) | 1.01 | A18 | A(13C-11C-16C) | 118.19 |
| R19 | R(10C—12C) | 1.43 | A19 | A(15C-11C-16C) | 121.66 |
| R20 | R(10C—17C) | 1.40 | A20 | A(10C-12C-15C) | 119.43 |
| R21 | R(11C—13C) | 1.47 | A21 | A(10C-12C-18C) | 117.66 |
| R22 | R(11C—15C) | 1.36 | A22 | A(15C-12C-18C) | 122.90 |
| R23 | R(11C—16C) | 1.49 | A23 | A(3O-13C-5 N) | 119.72 |
| R24 | R(12C—15C) | 1.43 | A24 | A(3O-13C-11C) | 123.37 |
| R25 | R(12C—18C) | 1.41 | A25 | A(5 N-13C-11C) | 116.89 |
| R26 | R(14C—20C) | 1.53 | A26 | A(5 N-14C-20C) | 112.53 |
| R27 | R(14C—34H) | 1.09 | A27 | A(5 N-14C-34H) | 108.22 |
| R28 | R(14C—35H) | 1.09 | A28 | A(5 N-14C-35H) | 105.88 |
| R29 | R(15C—36H) | 1.09 | A29 | A(20C-14C-34H) | 111.82 |
| R30 | R(16C—21C) | 1.41 | A30 | A(20C-14C-35H) | 109.79 |
| R31 | R(16C—22C) | 1.40 | A31 | A(34H-14C-35H) | 108.36 |
| R32 | R(17C—19C) | 1.41 | A32 | A(11C-15C-12C) | 121.81 |
| R33 | R(17C—37H) | 1.08 | A33 | A(11C-15C-36H) | 119.84 |
| R34 | R(18C—38H) | 1.09 | A34 | A(12C-15C-36H) | 118.34 |
| R35 | R(20C—39H) | 1.09 | A35 | A(11C-16C-21C) | 118.83 |
| R36 | R(20C—40H) | 1.10 | A36 | A(11C-16C-22C) | 122.59 |
| R37 | R(20C—41H) | 1.10 | A37 | A(21C-16C-22C) | 118.57 |
| R38 | R(21C—23C) | 1.40 | A38 | A(10C-17C-19C) | 119.12 |
| R39 | R(21C—42H) | 1.08 | A39 | A(10C-17C-37H) | 121.53 |
| R40 | R(22C—24H) | 1.39 | A40 | A(19C-17C-37H) | 119.35 |
| R41 | R(23C—25C) | 1.40 | A41 | A(6 N-18C-12C) | 124.55 |
| R42 | R(24C—25C) | 1.38 | A42 | A(6 N-18C-38H) | 116.14 |
| R43 | R(24C—43H) | 1.08 | A43 | A(12C-18C-38H) | 119.30 |
| R44 | R(26C—46H) | 1.09 | A44 | A(6 N-19C-7 N) | 115.99 |
| R45 | R(26C—47H) | 1.09 | A45 | A(6 N-19C-17C) | 122.69 |
| R46 | R(26C—48H) | 1.09 | A46 | A(7 N-19C-17C) | 121.32 |
| R47 | R(28C—29C) | 1.41 | A47 | A(14C-20C-39H) | 109.97 |
| R48 | R(28C—30C) | 1.41 | A48 | A(14C-20C-40H) | 110.02 |
| R49 | R(29C—31C) | 1.40 | A49 | A(14C-20C-41H) | 111.86 |
| R50 | R(29C—50H) | 1.09 | A50 | A(39H-20C-40H) | 108.15 |
| R51 | R(30C—32C) | 1.40 | A51 | A(39H-20C-41H) | 108.42 |
| R52 | R(30C—51H) | 1.08 | A52 | A(40H-20C-41H) | 108.33 |
| R53 | R(31C—33C) | 1.40 | A53 | A(16C-21C-23C) | 121.28 |
| R54 | R(31C—52H) | 1.09 | A54 | A(16C-21C-42H) | 119.93 |
| R55 | R(32C—33C) | 1.40 | A55 | A(23C-21C-42H) | 118.78 |
| R56 | R(32C—53H) | 1.09 | A56 | A(1Br-22C-16C) | 121.23 |
| R57 | R(33C—54H) | 1.08 | A57 | A(1Br-22C-24C) | 117.21 |
| A58 | A(16C-22C-24C) | 121.53 | |||
| A59 | A(8 N-23C-21C) | 125.98 | |||
| A60 | A(8 N-23C-25C) | 116.82 | |||
| A61 | A(21C-23C-25C) | 117.19 | |||
| A62 | A(22C-24C-25C) | 118.02 | |||
| A63 | A(22C-24C-43H) | 121.70 | |||
| A64 | A(25C-24C-43H) | 120.28 | |||
| A65 | A(2F-25C-23C) | 117.02 | |||
| A66 | A(2F-25C-24C) | 119.60 | |||
| A67 | A(23C-25C-24C) | 123.39 | |||
| A68 | A(7 N-26C-46H) | 111.25 | |||
| A69 | A(7 N-26C-47H) | 108.37 | |||
| A70 | A(7 N-26C-48H) | 111.30 | |||
| A71 | A(46H-26C-47H) | 109.16 | |||
| A72 | A(46H-26C-48H) | 107.57 | |||
| A73 | A(47H-26C-48H) | 109.16 | |||
| A74 | A(4O-27C-8 N) | 123.21 | |||
| A75 | A(4O-27C-9 N) | 124.17 | |||
| A76 | A(8 N-27C-9 N) | 112.62 | |||
| A77 | A(9 N-28C-29C) | 116.83 | |||
| A78 | A(9 N-28C-30C) | 123.65 | |||
| A79 | A(29C-28C-30C) | 119.52 | |||
| A80 | A(28C-29C-31C) | 120.48 | |||
| A81 | A(28C-29C-50H) | 119.74 | |||
| A82 | A(31C-29C-50H) | 119.78 | |||
| A83 | A(28C-30C-32C) | 119.26 | |||
| A84 | A(28C-30C-51H) | 119.58 | |||
| A85 | A(32C-30C-51H) | 121.15 | |||
| A86 | A(29C-31C-33C) | 120.24 | |||
| A87 | A(29C-31C-52H) | 119.45 | |||
| A88 | A(33C-31C-52H) | 120.31 | |||
| A89 | A(30C-32C-33C) | 121.35 | |||
| A90 | A(30C-32C-53H) | 118.75 | |||
| A91 | A(33C-32C-53H) | 119.90 | |||
| A92 | A(31C-33C-32C) | 119.16 | |||
| A93 | A(31C-33C-54H) | 120.36 | |||
| A94 | A(32C-33C-54H) | 120.48 |
The bond angles 1Br–22C–16C, 1Br–22C–24C, 2F–25C–23C, 2F—25C— 24C, 3O–13C–11C, 3O–13C–5 N, 10C–5 N–13C, 13C–5 N–14C, 10C–5 N–14C, 4O—27C, 4O–27C–8 N, 27C–8 N–45H, 27C–8 N–23C, 27C–9 N–49H, 27C–9 N–28C, 29C–28C–30C, 18C–6 N–19C, 6 N–19C–7 N, 19C–7 N–44H, and 19C–7 N–26C were 121.23°, 117.21°, 117.01°, 119.59°, 123.36°, 119.72°, 123.31°, 115.80°, 120.87°, 124.16°, 123.20°, 119.25°, 126.94°, 117.5690°, 128.0°, 119.52°, 117.58°, 115.99°, 118.47°, and 122.91°, respectively. The two halogens were in the meta positions of the middle aromatic ring, thus affording a unique structure.
3.2. FMO properties of ripretinib
FMO offers valuable information about the energy band gap. Thus, the various physical and chemical descriptors of the molecule, which enabled the elucidation of its reactivity, stability, and biological activity, could be predicted by the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies [35]. The energies were calculated at the B3LYP/6-311G + (2d,p) level of the theory. The excited states were calculated at the same level by TD-DFT. The frontier energies and other chemical descriptors were related [36,37], and the data are presented in Table 2 . HOMO and LUMO were in the 4-bromo-2-fluorophenyl and naphthyridin rings, respectively.
Table 2.
Ground- and excited-state energies of the molecule calculated at the B3LYP/6311 + (2d,p) level to describe the various chemical reactivity descriptors.
| Ground State | Excited State | |
|---|---|---|
| HOMO | −7.92 | −5.71 |
| LUMO | 2.20 | −1.66 |
| Energy gap, ∆E | 10.12 | 4.05 |
| Ionization energy (I = ɛHOMO = –HOMO) | 7.92 | 5.71 |
| Electron affinity (A = ɛLUMO = –LUMO) | −2.20 | 1.66 |
| Global hardness (η = (I − A)/2) | 5.06 | 2.03 |
| Global softness (S = 1/η) | 0.20 | 0.49 |
| Chemical potential (μ = −(I + A)/2) | −2.86 | −3.69 |
| Electronegativity (χ = −μ) | 2.86 | 3.69 |
| Electrophilicity index (ω = μ2/2η) | 0.81 | 3.35 |
| Nucleophilicity index (N = 1/ω) | 1.24 | 0.30 |
| ∆Nmax | 0.57 | 1.82 |
| Electroaccepting power, ω + = A2/2(I − A) | 0.24 | 0.34 |
| Electrodonating power ω + = I2/2(I − A) | −4.32 | −44.27 |
The ground- and excited-state properties are different. The energy gaps in the ground and excited states were 10.12 and 4.05 eV, respectively. This indicates that the excited state was less stable than the ground state, as expected. The free energies of the excited and ground states were − 3.69 and − 2.89 eV, respectively [16,[38], [39], [40]]. The electron-accepting power of the ground state was higher than that in the excited state, whereas the electrodonating power of the excited state is significantly higher than that of the ground state. This may be due to the triplet state of the excited state. Owing to the inherent instability of the excited state, the fraction of the charge that can be transferred is 1.82, and that, which can be transferred in the ground state, is 0.57 only. Therefore, there is increased electrophilicity in the excited state compared to in the ground state [[41], [42], [43], [44]].
3.3. Electronic spectra of the compound and light-harvesting efficiency
The electronic transition of ripretinib was studied by TD-DFT utilizing CAM-B3LYP functional and 6-311G + (2d,p) as the basis set in a methanol implicit solvent atmosphere employing the IEFPCM solvation model. The UV–Vis spectrum and the different orbitals involved in the transition are given in Fig. 2, Fig. 3 , respectively.
Fig. 2.
Simulated UV–Vis spectrum of ripretinib by TD-DFT/CAM-B3LYP/6–311 + G(2d,p) in methanol employing the IEFPCM model and exhibiting two distinct UV absorptions.
Fig. 3.
Pictorial representation of the various MOs involved in the electronic transitions. HOMO is in the central ring, while LUMO is delocalized over the naphthydrin group.
There are two prominent electronic transitions of the compound. The energy, wavelength, oscillator strength (f), and symmetry of the first transition are 32,154.32 cm−1, 311.00 nm, 0.58, and singlet asymmetry, respectively. The major contributions to these transitions (91%) are from HOMO to LUMO. HOMO is in the 4-bromo-2-fluorophenyl ring, and LUMO is in the naphthyridn one. Hence, the HOMO–LUMO transition involves electromigration from one region of the molecule to another, thereby inducing an intramolecular charge-transfer process. Regarding the second transition, the energy, wavelength, f, and symmetry are 39,373.03 cm−1, 253 nm, 0.32, and singlet asymmetry, respectively, with major contributions from the seventh lowest HOMO (HOMO-7) to LUMO, the second HOMO (HOMO-2) to LUMO, and HOMO to the second LUMO (LUMO +2) with 26%, 27%, and 13% contributions, respectively.
For the first transition, f was 0.58, which implies that the molecule possessed good light-harvesting efficiency (LHE) that is expressed as a function of f, as follows: LHE = 1–10−f [36,[45], [46], [47], [48], [49], [50]]. The value was 0.7376 for the first transition, which indicated that the compound could absorb 73.76% of incident-light energy for electronic excitation at that wavelength.
3.4. NLO properties of ripretinib
The study of light–matter interactions is very beneficial, especially for organic molecules. The ability of the molecule to bend the linear light can be determined by the polarizability and hyperpolarizability values, which were obtained from the simulation of the Raman spectra. These NLO activities are very beneficial to employing the compound in the organic electronics industry [[51], [52], [53], [54]]. The polarizability and hyperpolarizability data that were obtained during the simulation of Raman spectra were utilized for the estimation. The simulation was conducted at the same theoretical level as that of the optimization and compared with those of the standard NLO-active substance, urea [[55], [56], [57]]. The parameters of the NLO properties of ripretinib are shown in Table 3 .
Table 3.
NLO properties of ripretinib compared with those of a standard material (urea). The polarizability and hyperpolarizability data from the Raman simulation were utilized for their calculations.
| Nonlinear property | Ripretinib | Urea | Comparison with urea |
|---|---|---|---|
| Dipolemoment (μ) | 0.9804 D | 3.0482 D | 3.1091 times lower |
| Mean polarizability (α0) | 341.3780*10−23 esu | 35.6521*10−23 esu | 9.5752 times higher |
| Anisotropy of the polarizability (Δα) | 795.2260*10−23 esu | 69.0764*10−23 esu | 11.5122 times higher |
| Molar Refractivity (MR) | 8614.8331 esu | 899.6973 esu | 9.5752 times higher |
The dipole moment (μ), mean polarizability (α0), the anisotropy of the polarizability (Δα), and molar refractivity (MR) of ripretinib are 0.9804 D, 341.3780*10−23 esu, 795.2260*10−23 esu, and 8614.8331 esu, respectively, which are 3.1091 times lower than urea, 9.5752 times higher than urea, 11.5122 times higher than urea, and 9.5752 times higher than urea, respectively, when compared against those of the standard, urea. Thus, this molecule exhibits higher NLO properties than urea.
3.5. NBO of ripretinib
Intramolecular electron displacements are very essential because they determine the inherent stability of a compound. The NBO analysis is an excellent tool for studying such interactions via hyperconjugations [[58], [59], [60], [61]]. The occupancy values of NBOs and their delocalization energy avails valuable information on the aforementioned stabilities. NBOs were calculated with the NBO suite [62] that is available on the Gaussian-09 software.
Table 4 summarizes the delocalization energy during the electronic transitions. The electrons are transferred from the donor bonding orbitals to the acceptor antibonding orbitals with suitable occupancies utilizing energy, i.e., from σ (N6–C18) with an occupancy of 1.7872 to σ* (C10–C12) and σ* (C17–C19) with energies of 10.35 and 26.82 kcal/mol, respectively; from σ (C10–C12) with an occupancy of 1.5410 to σ* (N6–C18), σ* (C11–C15), and σ* (C17–C19) with energies of 33.68, 19.50, and 14.63 kcal/mol, respectively; from σ (C11–C15) with an occupancy of 1.7933 to σ* (O3–C13) and σ* (C10–C12) with energies of 25.98 and 12.56 kcal/mol, respectively; from σ (C17–C19) with an occupancy of 1.6378 to σ* (N6–C18) and σ* (C10–C12) with energies of 12.00 and 29.59 kcal/mol respectively; from σ (C22–C24) with an occupancy of 1.6861 to σ* (C16–C21) and σ* (C23–C25) with energies of 21.63 and 20.68 kcal/mol, respectively; from σ (C23–C25) with an occupancy of 1.6521 to σ* (C16–C21) and σ* (C22–C24) with energies of 18.32 and 23.88 kcal/mol, respectively; from σ (C28–C30) with an occupancy of 1.6392 to σ* (C29–C31) and σ* (C32–C33) with energies of 19.85 and 18.45 kcal/mol, respectively; from σ (C29–C31) with an occupancy of 1.7001 to σ* (C28–C30) and σ* (C32–C33) with energies of 21.93 and 18.45 kcal/mol, respectively; and from σ (C32–C33) with an occupancy of 1.6651 to σ* (C28–C30) and σ* (C29–C31) with energies of 20.55 and 24.06 kcal/mol, respectively.
Table 4.
Estimnated delocalization energy for different electronic trasitioms delocalisations in the molecule.
| NBOs | Donor NBO (i) | NBOs | Acceptor NBO (j) | Energy (in kcal/mol) | Occupancy |
|---|---|---|---|---|---|
| 10 | BD [2] N6-C18 | 292 | BD* [2] C10-C12 | 10.35 | 1.79 |
| 10 | BD [2] N6-C18 | 308 | BD* [2] C17-C19 | 26.82 | 1.79 |
| 22 | BD [2] C10-C12 | 280 | BD* [2] N6-C18 | 33.68 | 1.54 |
| 22 | BD [2] C10-C12 | 296 | BD* [2] C11-C15 | 19.50 | 1.54 |
| 22 | BD [2] C10-C12 | 308 | BD* [2] C17-C19 | 14.63 | 1.54 |
| 26 | BD [2] C11-C15 | 274 | BD* [2] O3-C13 | 25.98 | 1.79 |
| 26 | BD [2] C11-C15 | 292 | BD* [2] C10-C12 | 12.56 | 1.79 |
| 38 | BD [2] C17-C19 | 280 | BD* [2] N6-C18 | 12.00 | 1.64 |
| 38 | BD [2] C17-C19 | 292 | BD* [2] C10-C12 | 29.59 | 1.64 |
| 47 | BD [2] C22-C24 | 305 | BD* [2] C16-C21 | 21.63 | 1.69 |
| 47 | BD [2] C22-C24 | 319 | BD* [2] C23-C25 | 20.68 | 1.69 |
| 49 | BD [2] C23-C25 | 305 | BD* [2] C16-C21 | 18.32 | 1.65 |
| 49 | BD [2] C23-C25 | 317 | BD* [2] C22-C24 | 23.88 | 1.65 |
| 57 | BD [2] C28-C30 | 329 | BD* [2] C29-C31 | 19.85 | 1.64 |
| 57 | BD [2] C28-C30 | 336 | BD* [2] C32-C33 | 22.37 | 1.64 |
| 59 | BD [2] C29-C31 | 327 | BD* [2] C28-C30 | 21.93 | 1.70 |
| 59 | BD [2] C29-C31 | 336 | BD* [2] C32-C33 | 18.45 | 1.70 |
| 66 | BD [2] C32-C33 | 327 | BD* [2] C28-C30 | 20.55 | 1.67 |
| 66 | BD [2] C32-C33 | 329 | BD* [2] C29-C31 | 24.06 | 1.67 |
| 106 | LP [3] F2 | 319 | BD* [2] C23-C25 | 13.01 | 1.95 |
| 108 | LP [2] O3 | 277 | BD* [1] N5-C13 | 25.50 | 1.88 |
| 108 | LP [2] O3 | 294 | BD* [1] C11-C13 | 15.65 | 1.88 |
| 110 | LP [2] O4 | 286 | BD* [1] N8-C27 | 22.19 | 1.87 |
| 110 | LP [2] O4 | 288 | BD* [1] N9-C27 | 21.82 | 1.87 |
| 110 | LP [2] O4 | 315 | BD* [1] C21-H42 | 1.49 | 1.54 |
| 111 | LP [3] O4 | 117 | LP* [1] C27 | 286.47 | 1.54 |
| 112 | LP [1] N5 | 274 | BD* [2] O3-C13 | 54.25 | 1.60 |
| 112 | LP [1] N5 | 292 | BD* [2] C10-C12 | 44.45 | 1.60 |
| 114 | LP [1] N7 | 308 | BD* [2] C17-C19 | 51.50 | 1.72 |
| 115 | LP [1] N8 | 117 | LP* [1] C27 | 106.55 | 1.70 |
| 115 | LP [1] N8 | 319 | BD* [2] C23-C25 | 34.35 | 1.70 |
| 116 | LP [1] N9 | 117 | LP* [1] C27 | 114.22 | 1.70 |
| 116 | LP [1] N9 | 327 | BD* [2] C28-C30 | 31.82 | 1.70 |
| 274 | BD* [2] O3-C13 | 296 | BD* [2] C11-C15 | 50.01 | 0.37 |
| 280 | BD* [2] N6-C18 | 292 | BD* [2] C10-C12 | 255.94 | 0.37 |
| 280 | BD* [2] N6-C18 | 308 | BD* [2] C17-C19 | 242.87 | 0.37 |
| 292 | BD* [2] C10-C12 | 296 | BD* [2] C11-C15 | 117.36 | 0.51 |
| 317 | BD* [2] C22-C24 | 305 | BD* [2] C16-C21 | 184.42 | 0.41 |
| 319 | BD* [2] C23-C25 | 305 | BD* [2] C16-C21 | 122.92 | 0.45 |
| 319 | BD* [2] C23-C25 | 317 | BD* [2] C22-C24 | 385.89 | 0.45 |
The lone pairs of electrons were transferred from the bonding orbitals to the antibonding lone pairs of the antibonding orbitals, i.e., from the lone pair orbitals, n(F2), n (O4), and n(N7), with occupancies of 1.9463, 1.5404, and 1.7224, respectively, to the antibonding orbitals, σ* (C23–C25), n* (C27), and σ* (C17–C19), with energies of 13.01, 286.47, and 51.50 kcal/mol, respectively; from n (O3) with an occupancy of 1.8789 to σ* (N5–C13) and σ* (C11–C13) with energies of 25.50 and 15.65 kcal/mol, respectively; from n (O4) with an occupancy of 1.8708 to σ* (N8–C27) and σ* (N9–C27) with energies of 22.19 and 21.82 kcal/mol, respectively; from n (N5) with an occupancy of 1.5969 to σ* (O3–C13) and σ* (C10–C12) with energies of 54.25 and 44.45 kcal/mol, respectively; from n (N6) with an occupancy of 1.9150 to σ* (C12–C18) and σ* (C17–C19) with energies of 11.42 and 11.03, respectively; from n (N8) with an occupancy of 1.7035 to n* (C27) and σ* (C23–C25) with energies of 106.55 and 34.35 kcal/mol, respectively; and from n (N9) with an occupancy of 1.7000 to n* (C27) and σ* (C28–C30) with energies of 114.22 and 31.82 kcal/mol, respectively.
3.6. Molecular electrostatic potentials (MESP) map of ripretinib
The electrostatic potential, V(r), which is generated around a molecule by its nuclei and electrons and treated as static charge distribution, is a very beneficial property for studying and predicting molecular reactivity. This is narrowly defined and can be calculated experimentally and computationally. The capacity has been especially essential in indicating the positions or regions of the molecule where the advancing electrophile is initially drawn and has also been effectively extended to analyzing the associations that require a certain optimal relative orientation of the reactants, such as between the product and its cellular receptor [35,63,64]. MESP of the ripretinib molecule was generated from the data that was obtained from the previous calculation (Fig. 4 ).
Fig. 4.
MESP map of ripretinib indicating the surface-charge distribution contour.
The blue and red colors correspond to the numerical values between −0.1000 and 0.1000 and the molecule in the Bohr3 range of 17.08 to −22.50. The blue color corresponds to the oxygen atom (the electrophilic region) in the amide group, the fluorine atom in the phenyl ring, and the ketonic oxygen atom in the naphthyridin group, which are the electron-rich sites, indicating that the electrophiles could easily attack these sites. The red color corresponds to all the protons in the amide group (the nucleophilic region), bromine atom in the phenyl group, and all the protons in the methylamine group, which are electron-poor sites, indicating that nucleophiles can easily attack these sites.
3.7. ALIE property of ripretinib
The local, I(r), average ionization energy of ionization is the energy that is required to remove an electron from point r into the system. The lowest values represent the positions of the least tightly held electrons, which are, therefore, the selected reaction sites with electrophiles or radicals. Beyond its relevance to the reactive behavior, I(r) is significant in other fundamental fields, including atomic shell composition, electronegativity, and local polarizability and hardness [65]. ALIE of ripretinib is pictorially shown in Fig. 5 .
Fig. 5.
ALIE of the ripretinib molecule.
A color code can be employed to identify the ALIE surface of the molecule. The average volume of the molecule is in the −17.17 to −17.17 Bohr3 range. The bluish-green region indicates the delocalization of the electrons in the phenyl group, in the amide chain, from fluorine to the 4-bromo-2-fluorophenyl group, in the naphthyridin group, and in the methylamino chain, which produced several resonance structures that stabilized the molecule. The blue color indicates the sigma-bond, as well as the stable bond between the atoms in the ripretinib molecule, which are the protons to be attached to the methyl, ethyl, naphthyridin, and phenyl groups.
3.8. NCI property of ripretinib
NCI differs from a covalent bond because it does not involve the sharing of electrons, although it involves more dispersed variations of the electromagnetic interactions between the molecules or within a molecule. The three-dimensional arrangement of large molecules, such as proteins and nucleic acids, is crucial to NCI. Additionally, it is involved in many biological processes where large molecules bind to each other specifically but transiently. These interactions also significantly impact drug design, crystallinity and material design, self-assembling, and the design of the synthesis of tailored organic molecules [44]. The molecular structure of ripretinib was optimized and the multiwfn file was generated by DFT employing DFT-B3LYP as a method and 6-311G + (2d,p) as a basic set. NCI of ripretinib is shown in Fig. 6 .
Fig. 6.
Graph of NCI against the reduced density gradient and interaction energy.
A graph of energy against the reduced density gradient was plotted. The hydrogen bond appeared between −0.005 and − 0.021 a.u. from the hydrogen atoms in the amide nitrogen and the phenyl fluorine atom in the 4-bromo-2-fluorophenyl group. The van der Waals force attraction was observed in the range of −0.005 to 0.008 a.u. from the protons in the phenyl group to the amide oxygen and from the protons in the naphthyridin group to the ketonic oxygen. The steric force exists in the range of 0.008–0.25 a.u. involving the bromine atom in the 4-bromo-2-fluorophenyl group and the ethyl group in the naphthyridin group. All these interactions stabilized the system and ensured its reactivity toward biological systems.
3.9. Molecular docking
Scientists globally are researching drugs to manage the COVID pandemic. It is generally preferable to reroute existing drugs during this pandemic to save a lot of precious time that is required for new drug discovery. Therefore, we evaluated the activity of this drug against known COVID proteins. Molecular docking explains the structure-related activity of ripretinib against coV-2 proteins (PDB IDs:6M03 [66], 6 W63 [1], and 6 LU7 [1]) that have been deposited in the RSC database [33]. Table 5 explains the docking result between ripretinib and the coV-2 proteins (PDB IDs: 6M03, 6W63, and 6LU7), as follows: the 6 M03 protein possessed the highest inter-full fitness, ΔG ligand–solvent polarity, and total ΔG among the proteins. The 6 W63 protein possessed the highest surface-full fitness, ΔG complex–solvent nonpolarity, and ΔG protein–solvent nonpolarity among the proteins. Further, the 6 LU7 protein possessed the highest energy, simple fitness, full fitness, intra-full fitness, solvent-full fitness, ΔG complex–solvent polarity, ΔG protein–solvent polarity, and ΔG ligand–solvent nonpolarity among the proteins.
Table 5.
Docking results of ripretinib with coV-2 proteins.
| Parameters | 6 M03 | 6 W63 | 6 LU7 |
|---|---|---|---|
| Energy | 26.1878 kcal/mol | 25.2982 kcal/mol | 26.4866 kcal/mol |
| Simple Fitness | 26.1878 kcal/mol | 25.2982 kcal/mol | 26.4866 kcal/mol |
| Full Fitness | −1214.3522 kcal/mol | −1206.2007 kcal/mol | −1243.4666 kcal/mol |
| Inter-Full Fitness | −59.9006 kcal/mol | −47.326 kcal/mol | −41.9352 kcal/mol |
| Intra-Full Fitness | −4.05057 kcal/mol | −8.21465 kcal/mol | −8.64033 kcal/mol |
| Solvent-Full Fitness | −1368.99 kcal/mol | −1370.48 kcal/mol | −1411.76 kcal/mol |
| Surface-Full Fitness | 218.589 kcal/mol | 219.82 kcal/mol | 218.869 kcal/mol |
| Extra-Full Fitness | 0 kcal/mol | 0 kcal/mol | 0 kcal/mol |
| ΔG complex–solvent polarity | −1368.99 kcal/mol | −1370.48 kcal/mol | −1411.76 kcal/mol |
| ΔG complex–solvent nonpolarity | 218.589 kcal/mol | 219.82 kcal/mol | 218.869 kcal/mol |
| ΔG protein–solvent polarity | −1385.67 kcal/mol | −1372.14 kcal/mol | −1411.41 kcal/mol |
| ΔG protein–solvent nonpolarity | 221.3 kcal/mol | 222.123 kcal/mol | 221.095 kcal/mol |
| ΔG ligand–solvent polarity | −17.5824 kcal/mol | −15.3128 kcal/mol | −16.6198 kcal/mol |
| ΔG ligand–solvent nonpolarity | 8.95781 kcal/mol | 9.10841 kcal/mol | 9.12255 kcal/mol |
| ΔG van der Waals force | −59.9006 kcal/mol | −47.326 kcal/mol | −41.9352 kcal/mol |
| ΔG electric force | 0 kcal/mol | 0 kcal/mol | 0 kcal/mol |
| Total ΔG | −8.66 kcal/mol | −8.50 kcal/mol | −8.03 kcal/mol |
Ripretinib against the coV-2 proteins (6 M03, 6 W63, and 6 LU7) obtained the respective score values of 5242, 5328, and 5780; interaction areas of 578.70, 658.40, and 634.60; and minimum atomic contact energies of −192.77, −270.60, and − 288.10.
Fig. 7 shows the skeletal structure of the interactions between ripretinib and the 6 M03, 6 W63, and 6 LU7 proteins. Fig.S1 shows the interactions between ripretinib and the 6 M03, 6 W63, and 6 LU7 residues, and Table S1 presents the interactions of ripretinib with 6 M03, 6 W63, and 6 LU7. All the names of the protein residues and their labels, hydrophobicity, pKa values, average isotropic displacements, secondary structures, residue solvent accessibility, sidechain solvent accessibility, percentage solvent accessibility, and the percentage sidechain solvent accessibility values for interactions with ripretinib are presented in the table.
Fig. 7.
Skeletal structures of the interactions between ripretinib and the 6 M03, 6 W63, and 6 LU7 proteins.
Table S2 presents the nonbond interactions between ripretinib and the 6 M03, 6 W63, and 6 LU7 proteins with the distance, category, type, from chemistry, and to the chemistry of the favorable, unfavorable nonbond, and unsatisfied bonds within the ripretinib molecule.
Table 6 and Figs. S2, S3, S4, S5, and S6 show the noncovalent bonds between ripretinib and the coV-2 proteins (6 M03, 6 W63, and 6 LU7) and explain the hydrophobicity, hydrophilicity, neutral group-, acidic group-, and basic-group interactions, respectively.
Table 6.
Nonbond interaction labels between the coV-2 protein residues and ripretinib.
| Nonbond interactions | Names of the coV-2 proteins | Labels of the coV-2 proteins |
|---|---|---|
| Hydrophobicity | 6 M03 | THR A:24, THR A:26, LEU A:27, HIS A:41, VAL A:42, MET A:49, PHE A:140, LEU A:141, CYS A:145, MET A:165, and GLU A:166 |
| 6 W63 | HIS A:41, CYS A:44, THR A:45, SER A:46, MET A:49, MET A:165, GLU A:166, LEU A:167, PRO A:168, and GLN A:189 | |
| 6 LU7 | THR A:26, LEU A:27, HIS A:41, THR A:45, SER A:46, MET A:49, CYS A:145, HIS A:164, MET A:165, GLU A:166, and GLN A:189 | |
| Hydrophilicity | 6 M03 | THR A:24, THR A:26, HIS A:41, ASN A:142, GLU A:166, and GLN A:189 |
| 6 W63 | HIS A:41, THR A:45, SER A:46, GLU A:47, ASP A:48, GLU A:166, PRO A:168, ASP A:187, ARG A:188, GLN A:189, and GLN A:192 | |
| 6 LU7 | THR A:26, HIS A:41, THR A:45, SER A:46, HIS A:164, GLN A166, ASP A:187, ARG A:188, and GLN A:189 | |
| Neutral group | 6 M03 | THR A:24, THR A:25, THR A:26, SER A:46, GLY A:143, and GLY A:170 |
| 6 W63 | THR A:45, SER A:46, TYR A:54, PRO A:168, GLY A:170, and THR A:190 | |
| 6 LU7 | THR A:24, THR A:25, THR A:26, THR A:45, SER A:46, TYR A:54, and GLY A:143 | |
| Acidic groups | 6 M03 | THR A:24, THR A:26, and GLU A:166 |
| 6 W63 | GLU A:47, ASP A:48, GLU A:166, and ASP A:187 | |
| 6 LU7 | GLU A:187 and ASP A:187 | |
| Basic groups | 6 M03 | THR A:24, THR A:26, and HIS A:41 |
| 6 W63 | HIS A:41 and ARG A:188 | |
| 6 LU7 | HIS A:41, HIS A:164, and ARG A:188 |
4. Conclusions
We studied the structural features, energy features, energy descriptors, and other beneficial physical properties of ripretinib. The UV–Vis spectra exhibit a significant peak at 311 nm with f of 0.5812. From the NLO property of ripretinib, the mean polarizability and anisotropy of the polarizability are 9.5752 and 11.5122 times greater than those of the standard material, urea. The stability and intramolecular-charge delocalization were studied employing NBO. The properties of the reactive site, such as MESP, ALIE, and NCI, were detailedly explained, and it was confirmed that they occurred mostly in the amide oxygen, nitrogen, and protons in the phenylamide group; the fluorine and bromine and protons in the 4-bromo-2-fluorophenyl group; and the ketonic oxygen, methylamino, and ethyl protons in the naphthyridin group. Most significantly, the docking studies indicate that the molecule docks extensively with three important docking proteins (6 M03, 6 W63, and 6 LU7) that are related to CoV-2. Hence, this compound should be studied as a possible drug against SARS-n-CoV-2. ΔGs of the dockings of 6 M03, 6 W63, and 6 LU7 are − 8.66, 8.50, and − 8.03 kcal/mol, respectively, which are appreciable values. Thus, this compound could be developed as a drug to treat CoV-2 after screening via biological studies.
Credit authorship contribution statement
Fahad A. Alharthi : Simulation, data curation, writing original draft; Nabil Al Zaqri : Experiment design, Fund acquisition, Supervision; Ali Alsalme: Writing, reviewing and editing, Validation, Data analysis; Afnan Al-Taleb : Simulations, Validation; T. Pooventhiran.: Investigation, Simulation, Data curation, Writing- original drafts, Writing- revised draft; Renjith Thomas: Conceptualization, Methodology, Software, Supervision; D.J Rao: Simulations, Validation, Formal analysis.
Declaration of Competing Interest
Authors declare no conflicts of interest.
Acknowledgment
The authors extend their appreciation to the Deputyship for Research & Innovation, “Ministry of Education” in Saudi Arabia for funding this research work through the project number IFKSURG- 1440-141.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.molliq.2020.115134.
Appendix A. Supplementary data
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