key: cord-0693687-f9u80yu8
authors: Alsalme, Ali; Pooventhiran, T.; Al-Zaqri, Nabil; Rao, D. Jagadeeswara; Rao, Siriki Srinivasa; Thomas, Renjith
title: Modelling the structural and reactivity landscapes of tucatinib with special reference to its wavefunction-dependent properties and screening for potential antiviral activity
date: 2020-11-16
journal: J Mol Model
DOI: 10.1007/s00894-020-04603-1
sha: 2e59546ab82b95e86ec883e10c1fac6435160f8b
doc_id: 693687
cord_uid: f9u80yu8

HER-2 type breast cancer is one of the most aggressive malignancies found in women. Tucatinib is recently developed and approved as a potential medicine to fight this disease. In this manuscript, we present the gross structural features of this compound and its reactivity and wave function properties using computational simulations. Density functional theory was used to optimise the ground state geometry of the molecule and molecular docking was used to predict biological activity. As the electrons interact with electromagnetic radiations, electronic excitations between different energy levels are analysed in detail using time-dependent density functional theory. Various intermolecular and intermolecular interactions are analysed and reaction sites for attacking electrophiles and nucleophiles identified. Information entropy calculations show that the compound is inherently stable. Docking with COVID-19 proteins show docking score of − 9.42, − 8.93, − 8.45 and − 8.32 kcal/mol respectively indicating high interaction between the drug and proteins. Hence, this is an ideal candidate to study repurposing of existing drugs to combat the pandemic. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00894-020-04603-1.

Breast cancer is one of the most common type of neoplasm found in women and it is divided basically into different subtypes, viz., Luminal A, Luminal B, HER2-enriched, Basallike and the human epidermal growth factor receptor-2enriched (HER2-E) is indicated by the overexpression of growth factor receptor-related genes and cell cycle-related genes along with low presence of oestrogen-related and basal-related genes [1] [2] [3] . Always, there is a risk of metastatic spread to other interorgans like lungs, brain and bone [4, 5] .

HER2 tyrosine kinase inhibitor Lapatinib is widely used for the management of this disease [6] . Tucatinib is recently developed as a promising drug for the management of HER2positive breast cancer [7] . It is also used along with trastuzumab in patients with HER2-positive colorectal cancer [8] . Tucatinib even showed extensive anti-tumour activity and tumour regression in N87 gastric cancer cell line and HER2amplified colorectal, oesophageal and gastric cancers [9, 10] . The drug is also well tolerated in patients also along with trastuzumab [11] .

Recently, the new strain of coronavirus, n-CoV-2, is devastating human life in entire globe which now emerged to the dimensions of a pandemic and had impacted the life style and health of almost all the people [12] . Scientists through the globe are tirelessly working for establishing the pathology [13] , epidemiology [13] and many are try to develop novel molecules, antibodies and vaccines [14] . As it is difficult to come with a new magic molecule which could cure this disease in a short period of time, scientists are looking to reroute the existing drugs with known pharmacokinetics and pharmacodynamics for the management of COVID [15] [16] [17] . Chloroquine was once highlighted as a wonder medicine for the management of COVID, in spite of several differences in opinions about its effectiveness and now discontinued [18] . Remdesivir is now presently used widely to get rid of the pneumonia associated with COVID [19] . Lopinavir, umifenovir, favipiravir and oseltamivir molecules are also used now as a potentially active compound against the virus [15] . Thomas and coworkers recently reported that the sleep hormonemelatonin has preferential binding over the COVID proteins [20] . As it is time consuming to design and develop a drug for the treatment, it will be a wise decision to do research to reroute the existing drugs as a molecular target against the virus. We also thought in this direction and decided to screen tucatinib as a potential candidate for the management of COVID.

Understanding the electronic structure of a compound is very important for analysing the potential applications of a compound. Literature analysis showed that no studies have been reported in this direction. This manuscript attempts to study the detailed geometry, electronic structure, physical and chemical properties, orbital characteristics, surface topology, non-covalent interactions, electronic excitations, intermolecular stabilisations and information entropy analysis. It is followed by molecular modelling studies of the interaction of the molecule with four prominent n-CoV-19 proteins. We believe that this manuscript will be an addition to the scientific data.

We report the detailed study of the molecule using molecular simulations. Tucatinib molecule was optimised using Gaussian-09 [21] software, a package using DFT methodology with ωB97XD [22] [23] [24] functional and cc-pVDZ basis set [25] . We performed the frequency calculations to ensure that there exists no imaginary frequency such that the obtained geometry corresponds to a global minimum for reaching the optimised geometry. We used the same geometry for calculating frontier molecular analysis, natural bonding orbitals and non-linear optical studies. For UV-visible spectrum simulation, we used time-dependent density functional theory (TD-DFT) with long-range corrected CAM-B3LYP functional [26, 27] and aug-cc-pVDZ basis set as the electronic transitions are time-dependent phenomena with GaussSum [28] . Reaction sites of tucatinib calculated using Multiwavefunction [29] software for calculating total electrostatic, average localised ionisation energy, electron localisation functions, localised orbital locator, reduced density gradient, localised entropy interaction, electron delocalisation functions, local electron locator, reduced density gradient and non-covalent interactions for tucatinib's anti-coronovirus2 biological activity were analysed by using suitable proteins in the PDB format downloaded from RCSB [30] site, the energy received from SwissDock and the score values received from PatchDock [31] after docking and the docked results analysed using bio-discovery studio.

Geometry structure for tucatinib Tucatinib molecular structure was optimised by using density functional theory method for structural confirmation, DFT-ωB97XD as a method, and cc-pVDZ as a basis set. The optimised structure for tucatinib is shown in Fig. 1 and Table 1 shows important bond distances and angles for Frontier molecular orbital (FMO) properties for tucatinib Frontier molecular orbitals can provide valuable information the energy band gap and using the HOMO and LUMO energy, one can predict various physical and chemical descriptors of the molecule, which enables us to comment on the reactivity, stability and biological activity [32] . The energies are calculated in the DFT-ωB97XD/cc-pVDZ basis set and the related data is presented in Table 2 . HOMO is the molecule is found to have energy − 5.59 eV and LUMO − 1.50 eV. The energy gap is only 4 eV. The ionisation energy [33, 34] is 5.50 eV and electron affinity 1.59 eV [35] [36] [37] [38] . Global hardness [39, 40] and softness [41] are widely regarded as an indicator of the reactivity of compounds, whose values are 2.00 eV and 0.50 eV respectively. The softness value is high such that the compound is polarisable and hence more chance to be biologically active. The chemical potential, which is the average of ionisation energy and electron affinity is found to − 3.59 eV, which indicates that the molecule is reactive [42] . The electronegativity [43] was 3.59 eV. The compound is electrophilic (see the [44, 45] and nucleophilicity index [46] [47] [48] [49] values) in nature with a negative electrondonating power. This is in agreement with the high electron affinity values. Hence, it can be concluded that the compound is inherently reactive and this feature is responsible for various biological activities.

Being a time-dependent phenomenon, the electronic transitions and consequently the electronic spectra of compounds cannot be modelled by DFT simulations, instead has to use time-dependent (TD-DFT) simulations which employs Tamm-Dancoff approximations [50, 51] . We used TD-DFT simulations with CAMB3LYP functional and cc-pVDZ as a basis set using IEFPCM [52] solvation model with methanol as solvent. The ultraviolet-visible spectrum and the different orbitals involved in the transition are given in Figs. 2 and 3 and Table 3 .

Simulation shows that there are three electronic transitions possible and among them, only two are significant. The first peak was observed at wavelength is 309.24 nm with oscillator strength is 0.44. It is with singlet asymmetry and the major reasons of this peak is the transition from higher occupied molecular orbital (HOMO) to lower unoccupied molecular orbital (LUMO) with 90 percentage contribution. The second significant peak was at 267.56 nm with oscillator strength of 0.26, and singlet asymmetry. This peak is due to electronic transitions from second last higher occupied molecular orbital (HOMO-2) to lower unoccupied molecular orbital (LUMO) with contribution 12 percentage, and from higher occupied molecular orbital (HOMO) to second lower unoccupied molecular orbital (LUMO+2) with 60 percentage contribution. For the first transition, oscillator strength ( f ) is 0.4431, which means, the molecule is having good light-harvesting efficiency (LHE), which is expressed as a function of the oscillator strength related as LHE = 1-10 -f [53] [54] [55] [56] . The value is 0.6395 for the first transition, which indicate that the compound can absorb 63.95% of the incident light energy for electronic excitation at that particular wavelength [57, 58] .

Study of light matter interactions is very important especially for organic molecules. Recently, a large number of organic non-linear optical (NLO) compounds have been extensively studied using various computational tools for their potential industrial use [59] [60] [61] . The ability of the molecule to bend the linear light can be done using the polarisability and hyperpolarisability values obtained from the Raman spectrum simulation. This type of non-linear optical activity is very important for using the compound in organic electronics industry [62] [63] [64] . The simulation is carried out in the same theoretical level as of the optimisation and is compared with a standard non-linear optically active substance urea and pnitroacetanilide (PNA) [65, 66] . The non-linear optical property parameters for tucatinib are shown in Table 4 . Tucatinib is found to have dipole moment (μ) of 2.74 D, which is 1.58 times greater than urea and 3.01 times greater than p-nitro acetanilide. Hyperpolarisability (β) is 51.60*10 −31 e.s.u., which is 6.79 times greater than urea and 0.21 times than pnitro acetanilide. The high values of values are due to the highly non-symmetric structure of the compound (C s point group).

Intramolecular electron displacements are very important as they decide the inherent stability of a compound. Natural bond orbital analysis is an excellent tool to study such interactions via hyperconjugation [67] [68] [69] [70] [71] [72] . The occupancy values of the natural bond orbitals and their deloclaisation energy provide valuable information about the above-mentioned stabilisations. Nature bond orbital (NBO) calculations were done using the NBO suite available within the Gaussian 09 software. Table S1 shows the natural atomic orbital (NAO) occupancies for tucatinib. In general, the decreasing order of atomic orbitals by the occupancies are core orbital > valence orbital > Rydberg orbital. Table S1 shows the number of atomic orbitals, the symbol of atoms, number of atoms, angular momentum, type of atomic orbital, occupancies, and energy in a.u. unit Tucatinib having 624 nature atomic orbitals (NAOs), the oxygen atoms label numbers from 1 to 2 atoms nature atomic orbital numbers are 6, 18 having py, and px angular momentum with atomic orbital type is valence 2p, occupancies are 1. 40 Table S2 provides the summary of natural population charge analysis for tucatinib. Each atom having particular natural charges and population charges is core, valence and Rydberg populations. Tucatinib molecule's total natural charge is zero, and total natural populations in the core is 71.97, valence is 179.24 and the Rydberg population is 0.79 and the total population is 252.00. Table S3 shows the natural populations between natural minimal basis and natural Rydberg basis for tucatinib. Total core population is 71.97 out of 72 basis, which is more than 99.50 percentage; valence population is 179.24 out of 180 basis, which is more than 99.50 percentage; the natural minimal basis (NMB) is 251.21 out of 252 basis, which is more than 99.50 percentage; and natural Rydberg basis (RYB) is 0.79 out of 252 basis, which is below 0.50 percentage. Table S4 shows the electronic configurations for all the elements in tucatinib. Table S5 explains natural bond analysis by occupancy threshold energy for in tucatinib. For the cycles 1 and 2, having the same occupancy threshold energy 1.9, Lewis occupancy is 238.24, non-Lewis occupancy is 13.76 and deviation is 0.63. Table S6 shows the total Lewis and non-Lewis contributions for tucatinib. The contributions for core orbital are 71.97 out of 72 basis, which is more than 99.50 percentage, valence Lewis orbital is 173.56 out of 180 basis, which is 96.42 percentage and total Lewis contribution is 245.53 out of 252 basis, which is 97.43 percentage. The contribution of valence non-Lewis orbital is 5.92 out of 252 basis, which is 2.35 percentage, Rydberg non-Lewis orbital is 0.55 out of 252 basis, which is 0.22 percentage and total non-Lewis contribution is 6.47 out of 252 basis, which is 2.57 percentage. Table S7 explains nature bond orbitals (NBOs) using second-order Perturbation theory analysis of Fock matrix in NBO Basis. This table explains various electrons transfers from donor natural atomic orbitals to acceptor natural atomic orbitals by labels and absorption energies. All these electron delocalisations lead to inherent stability of the molecule [73] .

The local I(r) average energy of ionisation is the energy needed to remove an electron from point r the system. The lowest values show the positions of the least tightly held electrons and therefore the chosen reaction sites by electrophiles or radicals [74] [75] [76] [77] . The 2D representation of average localised ionisation energy (ALIE) of tucatinib is given in Fig. 4 .

The colour greenish-blue is denoted delocalised electrons appearing in 4,4-dimethyloxazole, 4,4-dimethylozazolamin, quinazolin, quinazolinamin and triazolepyridin groups; these are giving the number of resonance structure and explain stability of tucatinib. The colour blue is denoted sigma or stable bonds occur in all the carbons, which are having protons. The colour red indicates multiple bonds; fortunately, there are no multiple bonds present in the tucatinib.

This study explains the electronic structure for tucatinib. The higher value of electron localisation function is strongly localised and low value is strong delocalisation of electron in this molecule [78] [79] [80] . The electron localised function (ELF) for tucatinib is shown in Fig. 5 . Tucatinib has the range between − 16.34 and 16.34 Bohr 3 , the probability value between 0.000 and 1.000, and the colour blue to red shown in Fig. 5 .

The red in colour shows that high probability to strong пlocalised electrons occurs on the carbon, nitrogen and oxygen atoms core and lone-pair of electrons, and all the protons in the molecule. The blue in colour shows that high probability to 

Localised orbital locator (LOL) study explains the orbital locations for tucatinib [81, 82] and is represented in Fig. 6 . The value ranges between − 16.34 and 16.34 Bohr 3 , values between 0.000 and 0.800, and colour from blue to red shown in Fig. 6 . The colour red denotes strongly localised п-orbitals which occur between carbons and oxygens, carbons and nitrogens, and carbons and carbons in 4,4-dimethyloxazolamin, quinolinamin, methylphenyl and triazoxylpyridin groups. The colour blue denotes strong delocalised п-orbitals which occurs in 4,4-dimethyloxazolamin, quinolinamin, methylphenyl, triazoxylpyridin rings and all the hydrogens in the whole molecule. The electrostatic potential V(r) generated around a molecule by its nuclei and electrons which are treated as static charge distribution is a very useful property for studying and predicting molecular reactive actions [83] [84] [85] [86] [87] . The capacity has been especially useful as an indication of the positions or regions of the molecule to which the advancing electrophile is initially drawn, and has also been effectively extended to the analysis of associations requiring a certain optimal relative orientation of the reactants, such as between the product and its cellular receptor. Tucatinib molecule's MESP was generated using the data obtained in the previous calculation and is represented in Fig.7 . Figure 7 shows those sites within the range between − 16.26 and 16.26 Bohr 3 , the numerical value from − 0.100 to 0.100 and the colour from blue to red.

The colour blue on all the nitrogen atoms in amin-oxazole and amin-quinazolin groups is electron-rich sites, and therefore electrophiles can easily attack these sites. The colour red on all the carbons which are having protons in 4,4-dimethylozalol, quinazolin, 2-methylphenolat and triazolepyridine groups is electron-poor sites, and therefore nucleophiles can easily attack these sites.

The electrostatic potentials from nuclear charges [85, 87] for tucatinib are shown in Fig. 8 . Tucatinib has the range between − 15.88 and 17.67 Bohr 3 , values between 0.000 and 0.800, and colour from blue to red shown in Fig. 8 .

The colour red denotes negative electrostatic potentials between the range 47.000 and 50.000 and shows strong attraction between protons and nuclei core and lone-pair of electrons in carbons, nitrogens and oxygens in 4,4dimethyloxazolamin, quinazolinamin and triazoxylpyridin groups. The colour blue denotes positive electrostatic potentials between the range 15.000 and 23.000 and shows strong repulsions between protons and nuclei in all the hydrogens in the whole molecule.

The reduced density gradient is directly proportional to the electronic density of the molecule. Which means a small reduced density gradient is low electronic density [88] [89] [90] [91] [92] . Figure 9 shows the reduced density gradient for tucatinib. Tucatinib has the range between − 14.88 and 16.34 Bohr 3 , values between 0.000 and 1.000, and colour from blue to red shown in Fig. 9 .

The colour red range between 0.800 and 1.000 shows the most probability of the reduced density gradients which occur in higher molecular weight elements which are oxygens, nitrogens and carbons in 4,4-dimethyloxazolamin, quinolinamin, methylphenyl and triazoxylpyridin groups.

This study explains the stability of the molecule. Entropy is a feature of probability distributions and can take to be a qualification of uncertainty. The high value of local information entropy is directionally proportional to the uncertainty of electrons in spatial distribution [93, 94] . Figure 10 shows local Fig. 6 Localised orbital location for tucatinib information entropy for tucatinib. Tucatinib has the range between − 16.34 and 16.34 Bohr 3 , values between 0.000 and 0.100, and colour from blue to red shown in Fig. 10 .

The colour blue shows the entropy value between 0.000 and 0.015 which denotes low uncertainty regions in 4,4dimethyloxazolamin, quinolinamin, methylphenyl and triazoxylpyridin groups. The colour bluish-green shows the moderated entropy values between 0.035 and 0.045 which denotes moderated uncertainty of the elements which are carbons, nitrogens and oxygens in 4,4-dimethyloxazolamin and quinolinamin groups.

A non-covalent interaction differs from a covalent bond by not involving the sharing of electrons but involving more dispersed variations of electromagnetic interactions between molecules or within a molecule. The threedimensional arrangement of large molecules, such as protein and nucleic acids, is important to non-covalent interactions. Additionally, they are also involved in many biological processes where large molecules bind to each other specifically but transiently. These interactions also have a strong impact on drug design, crystallinity and material design, self-assembly and the design of synthesis of tailor-made organic molecules [89, 95] . The non-covalent interactions for tucatinib are shown in Fig. 11 .

This study explains the non-covalent bonds which occur in the molecule. Figure 11 shows the non-covalent bonds which are hydrogen-bond, van der Waals and steric force type of bonds which occurs in the tucatinib; a graph plotted energy against reduced density gradient.

The hydrogen bonds appear between the range − 0.020 and − 0.005 a.u. from secondary amin-nitrogen attached in 4,4dimethyloxazol to hydrogens in methyl in 4,4-dimethyloxazol and quinazolin groups, and from secondary amin-nitrogen attached in quinazolin to hydrogens in quinazolin and 2methylphenoate groups, the van der Waals force between the range − 0.005 and 0.003 a.u. from oxygen in 2methylphenolat to hydrogens in methyl in 2-methylphenoate and triazolepyridin groups, and steric force between the range 0.004 and 0.050 a.u. within the rings for 4,4-dimethyloxazol, Fig. 9 Reduced density gradient for tucatinib Fig. 10 Local information entropy for tucatinib quinazolin, 2-methylphenoate and triazolepyridin groups, and between 4,4-dimethyloxazol and quinazol, quinalolin and 2methylphenolat, and 2-methylphenolat and triazolepyridin groups.

Scientists around the globe are looking medicines for managing the COVID pandemic. It is always better to reroute the existing drugs for this pandemic as it could save lot of precious time for new drug discovery. We also thought in this direction and checked the activity of this drug against known COVID proteins. Molecular docking can be used as a tool to screen the biological activity of a compound [96, 97] . Molecular docking explains the structure relative activity of tucatinib against coronovirus2 proteins (PDB IDs: 6M03 [98] , 6W63 [99] , 6LZG [100] and 6LU7 [99] ) deposited in the RSC database [30] . Figure 12 shows the skeletal structure and residues with labels of interactions between tucatinib with coronovirus2 proteins, and Table S8 explains the coronovirus2 protein labels, name, hydrophobicity, pKa, average isotropic displacement, secondary structure, residue solvent accessibility, sidechain solvent accessibility, percent solvent accessibility and percent sidechain solvent accessibility values. Table S9 explains the non-covalent bonds which occur between tucatinib with coronovirus2 proteins are favourable non-bond, unfavourable non-bond and unsatisfied bond within tucatinib interacting with coronovirus2 proteins. Table S8 explains the non-covalent bonds are hydrophobicity, hydrophilicity, neutral, acidic and basic group label interactions between tucatinib with coronovirus2 proteins. Figure S1 , Table S2 and Table 4 explain the water-resistant as well as called hydrophobic interactions between tucatinib with coronovirus2 proteins. Figure S2 , Table S9 and Table 6 show water-loving groups of interactions between tucatinib with coronovirus2 proteins. Table S9 and Table 6 with 

Tucatinib molecule having good HOMO-LUMO values, which show good chemical parameters energy gap, ionisation energy, electron affinity, global hardness, global softness, chemical potentials, electronegativity, electrophilicity index and nucleophilicity index. From the UV-Visible spectrum result, tucatinib has shown absorption peaks at 309.1468 and 267.5687 nm with 0.4431 and 0.2633 oscillator strengths.

From the NLO property of tucatinib, the dipole moment is 2.1797 times greater than urea and 7.9092 times greater than p-nitro acetanilide, hyperpolarisability is 10.9881 times greater than urea and 1.2032 times greater than p-nitro acetanilide, mean polarisability is 15.3529 times greater than urea and 3.0367 times greater than p-nitro acetanilide, the anisotropy of the polarisability is 16.9187 times greater than urea and 2.5999 times greater than p-nitro acetanilide, and molar refractivity (MR) is 15.3494 times greater than urea and 3.0360 times greater than p-nitro acetanilide. The NBO result explains the molecular bonding property of tucatinib having suitable occupancies with energies. The reaction site properties were electrostatic potentials, average localised ionisation energy and non-covalent interactions mostly occur on 4,4- 

Conflict of interest The authors declare that they have no competing interests.

Consent to participate NA.

Code availability NA. 

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