Crystallographic Principal Modulation and Metal Core – Crystal Structure Exchangeable: Computational And Molecular Docking Simulation

Keeping in mind, the structural analysis can be modied and regulated with computational background then advances in complex structural analysis thereof. Crystallographic data of metal complexes can be modulated to form a huge number of other metal complexes that can be synthesized and applied in recent further elds. The crystal structure of Pd complex was studied as previously reported and identied to be exchanged with other metals such Zn and Ni. DFT methodology was applied to investigate the difference in electronic properties of these complexes-exchangeable metals. Spectroscopic studies were performed to compare the difference in results. Hirschfeld surface analysis deeply illustrated the intermolecular contacts of the reported Pd crystal structure. Molecular docking simulation was applied on the previously synthesized complex and the investigated ones using E-coli protein target with comparison in details.


Introduction
Transition metals, that represent the core of coordination chemistry, are used in several purposes such catalytic and biological antitumor elds. These applications stimulate the researchers to think in more advance of modulation larger molecular systems perform the same behavior like analogues [1]. Several studies on platinum complexes succeeded in exploring them as a proved drugs as antitumor agents [2,3].
Palladium is a soft lewis acid like platinum and have similar biological and thermodynamic properties, due to this reason, palladium-based compounds were synthesized and gave a large area for studying their biological behavior [4,5].
Several interesting works in the literature were recently reported measuring different intensities in palladium-based complexes activity on species variations like fungi and bacteria [6][7][8][9][10]. It was recently demonstrated that palladium (II) complexes including a thiazoline derivative ligand helped in reduction of proliferation capacity also induced apoptosis in the cell lines of colon HT-29 and lymphoma U-937 [11]. Coordinated ligand modi cations in metal center also enhance the cytotoxic activity of metal complexes [12][13][14].
Examining the geometrical structure of most Pd-complexes, it was found that 4-bonded coordinated structure locate between tetrahedral and square planar geometrical pathway depending on the electronic con guration of the metal. Also, a mutual arrangement around the planar environment basically depends the interacting molecular orbitals resulting the implementation of optimal planar geometry of the compound causing ligand-ligand charge transfer reactions [15][16][17] To view of mentioned above, researches move towards the molecular design study of many metal complexes preferring the square-planar structure.
The widespread availability on compound transformation and atoms rearrangement with different computational approaches open the door to exploring and investigating different models may be carry signi cant properties help in several aspects. Drug design can export the same meaning of metalcoordination modulated compounds.
Density functional theory (DFT) methods are a strong and powerful computational technique in molecular modeling and drug design. Beside metals, ligands act as heterocyclic chelated systems help strongly in investigating the bioactive systems in pharmaceutical and medicinal applications.
The aim of this current study motivates investigation of metal-core complexes with distinguishable properties which lead to preference of metal complexes crystal structure synthesis but no other formed.
Crystallographic modi cation structure gives new results about the formation of the crystal structure. Pdheterocyclic framework was selected as a synthesized crystal structure to implement and design a structure model with different metals such Zn and Ni. These types of metals were selected according to their ultra-ability in forming complexes with different heterocyclic ligands with different geometries.

Experimental background
X-ray data of Pd-morpholine derivative complex was translated in a CIF le which was signi cantly downloaded from the Crystallography Open Database (COD), http://www.crystallography.net. These data are publicly available for researchers in order to make investigation and modi cations leading to further study. Pd-complex CIF le was read in mercury software to detect the short contacts in the crystal unit especially intra and intermolecular H-bond formation. From the data gathered, it was found that palladium has a square planar geometrical structure with bidentate chelating ligand and two coordinated Cl atoms [18].
According to the mode of binding, the metal-complexes in Fig. 1 occur in the cis isomer and face di culties in trans-isomer synthesis. The chelating morphine derivative ligand bind with the mode to be di cult undergoes rotation. Also, the aliphatic and aromatic ring strains hinder the structure transformation. Exchanging of Pd from second raw of periodic table with Ni in the rst raw but at the same group with similar general electronic con guration can explore other synthesized Ni-complexes have the same electronic behavior like Pd-complexes. Also, exchanging of Pd-complexes with other rst raw periodic table metal such Zn in other group give the chance to investigate its comparable crystallographic behavior.

Computational advances
Powerful supported computational programs were used in this study. Guassian 09 software [19] was applied on the X-ray structure of Pd complex and its modi ed crystallographic data included using B3LYP/LanL2DZ method that involve a wide range of molecular systems calculations especially metal core complexes [20]. Guass view [21] and mercury 4.0 software [22] were used for output structure visualization, atom labelling and color editing. Molecular docking simulation was applied using iGemdock software [23] under the default setting. E-coli expression system was selected for this analysis, where the types of organisms responsible for bacterial infection are Listeria monocytogenes protein target of PDB 1O6S and Brucella suis protein target of PDB 2BHM were downloaded from the protein data bank (https://www.rcsb.org/) as a PDB le. There was a preparation step in which water, ions and any extra useful species should be removed from the receptor. The investigated guest complexes were used in their optimized structure. Hirschfeld and different ngerprint plots were studied using crystal explorer 21.5 program [24]. The results originated from the crystallographic le of Pd-morpholine derivative complex.

Experimental work investigation
As shown in Fig

DFT crystallographic modulation
To compare between the modulated metal structures with the experimental data, Table 1 presents some important geometrical bond lengths and bond angles of the studied complexes. The observed X-ray geometrical indices were compared with the calculated results using DFT/B3LYP/LanL2DZ effective method in gas phase. The experimental Pd1-S2, pd1-Cl3, Pd1-Cl4 and Pd1-N5 bond lengths have values 2.260, 2.328, 2.293 and 2.102 Å, respectively. There is a satis ed computational result with the experimental ones except in case of Zn-morpholine complex in which Zn1-S2 bond length is 2.692Å. This difference may be attributed to the weak bond formed between Zn atom and S atom of the ligand destroying the molecular stability of the unit cell structure. X-ray bond angles of S2-M1-Cl3, S2-M1-Cl4, evaluating the bond angles of the studied complexes, it was found the computational results of Pdcomplex move in the same trend leading to formation of a square planar structure, also, in case of Nicomplex the data calculated are relatively closer to P-complex indicating a square planar Ni-complex formation. On the contrary, the data investigated for Zn-complex not as the same in both Pd-and Ni structures. Bond angles values in Zn-complex insight a tetrahedral structure formation. Fig. 3 illustrates theoptimized structures of the studied complexes with full labeled atoms. To examine the natural bond orbital analysis, the atomic charges of the compound must be in the full optimized state till reach the ground state stationary point.   The data calculated present in Table 3 where the dipole moment values indicate whether is most polarizable compound. Pd-complex show higher dipole moment value (13.335) then Ni-complex (12.838) and the the lower is of Zn-complex (10.877). the relation between these parameters and stability of compounds can mainly help in the chemical reactions whose these compounds associated [25] The frontier molecular orbitals (FMOs) of Pd-complex occur in levels with energies enough to motivate compound stabilization (E GAP = 5.74 ev) through electron transition where it is relatively small compared with the other complexes. Also, other parameters signi cantly control the compounds stability and reactivity such as ionization potential (I), electron a nity (A), chemical potential (µ), chemical hardness (η) and global softness (σ) were calculated and tabulated. Also, a helpful polarizability index (α) was calculated and indicated that Pd-complex is the most polarizable molecular structure (207.089). Figure 4 shows the FMOs of the studied complexes with the energy of each level where the highest occupied molecular orbital (HOMO) contribution is mainly on the whole coordinated N ring bearing O atom in both Pd and Ni complexes, but this contribution not appear in Zn-complex. This aimed to that Pd and Ni-morpholine derivative complexes mostly act in the same as structural and electronic behavior.

IR Spectroscopic analysis
Differences in spectroscopic data analysis between the modulated and reported structures seem to be simple. Fig. 5 shows DFT/IR and Raman spectral bands obtained for the reported Pd complex and the modulated Zn-, Ni-complexes. Vibrational frequencies were taken in the range of 500-4000 cm -1 and were performed by normal modes that corresponding to the ground state molecular electronic structure [26,27].
The characteristic bands of the three studied molecular structures varies in their absorbance and scatter intensity from strong into weak contribution. Very simple variations in the peak position and intensity especially the position of M-coordinated atom peak due to the electronic environment surrounded by the band group. Mostly in all studied cases, the peaks appear in the position range 3238cm -1 -3216cm -1 are corresponding to =C-H aromatic group, whereas the peaks located at 3181cm -1 -3007cm -1 are characteristic to -C-H aliphatic group. C=C stretching peak appear at 1626 cm -1 . The observed peak at 1313 cm -1 is attributed to C-O stretching bond analysis. There are also some weak peaks appear in the range 1081cm -1 -1057cm -1 that corresponding to C-C and C-N stretching single bonds. The band at 614 cm -1 is corresponding to C-S bond. A strong peak appears at 1523 cm -1 is corresponding to -C-H bending.
Pd-N stretching band appears at 549 cm -1 . Pd-Cl appears at 346 cm -1 but not occur in the computational scale. Ni-N band occurs at 552 cm -1 , while Zn-N band appears at 536 cm -1 .

UV-Vis spectra detection (TD-DFT)
CPCM model in DT-DFT method is best describe the behavior of electronic transitions in the molecular structure. Fig. 6 shows the different transition states for the studied optimized Pd, Zn and Ni complexes. It was observed that there are three transitions with different excitation environment. Mentioned to UV/Vis spectra of Pd-complex, the orbital contribution in the three transitions involve HOMO-2, HOMO-1 and HOMO to only LUMO state. This case indication about the limitation of electron transfer to higher unoccupied states and that must need higher absorption energy for successive electronic transitions. In case of Ni-complex, the peaks appear in higher wavelength range with small absorbance values, that may be increasing the di culty for Ni-morpholine derivative crystal structure formation in the same condition of Pd-complex synthesis. The orbital contribution as the same in Pd-complex in transition to only LUMO level while there are successive transitions between HOMO and its lower states. In case of Zn-complex, UV/Vis spectra appeared at lower wavelength higher absorbance. These transitions are allowed for the ligand intra-excitation states (n-π* and π-π*) but d-d transition, that distinguish the metal-ligand transition, not observed. The excitation energy for each transition and orbital contribution are tabulated in Table 4.

Hirschfeld surface analysis of Pd-complex structure
This type of analysis discusses the percent quantity of crystal structure intermolecular contacts represented with red spots. Fig. 7 shows these surface analytical contacts for Pd-complex. 3D-ngerprint plots in Fig. 8 give evolution about the percent atom pairs contacts where all the contact atom pair types present as a whole percent 100%. The close contact between the inside Cl layered atom to the outside H atom gives 18.4%. The inside O to outside H gives 3.5%, while the inside S atom to outside H atom gives 2.5% contact.
The crystal packing of Pd-complex (unit cell dimensions 1:1:1) present in Fig. 9 as the close intermolecular contacts are represented in red lines. The maximum bond distance of these contacts was chosen as 2.70 Ǻ where there are different types of atom pair intermolecular contacts. Increasing the contact distance (> 2.70 Ǻ), larger types of interactions appear around the crystal structure of Pdcomplex. Due to different types of heteroatoms, the crystal structure packing is strong between the molecules and that lead to a signi cant arrangement of the crystal structure [28].

Molecular docking simulation
As a part of molecular behavior for complexes toward the biological inhibition process, the studied metalmorpholine derivative complexes were docking investigated in binding with 1O6S and 2BHM receptor codes. Figure 10 visualizes the molecular docking of the three studied metal-complexes with either 1O6S and 2BHM protein receptors. Furthermore, the best explored 1O6S results of molecular docking for Ni-and Znmorpholine derivative complexes located in the same position pocket with total tting energy of -59.80 Kcal/mol and -58.70 kcal/mol while the previously synthesized Pd-morpholine derivative complex in other protein position with total docking score of -60.300 kcal/mol. For the three complexes, the docking score energies are signi cantly the same but the difference in the type and number of bound protein amino acids. As shown from Table 5 Table 6, the total score energy for Pd-,Ni-and Zn-complexes are -64.800, -65.400 and -61.200 kcal/mol. Pd-complex is surrounded by 7 types of binding amino acids, but Ni-and Zncomplexes are surrounded by 6 binding amino acids in the target pocket.

Conclusion
The metal-core exchangeable X-ray structure exported some important investigations related to different properties of the exchanged metal atoms, for example, the electronic and orbital con guration of the metal can alter the crystal structure and mode of binding. Pd-complex previously exhibit a distorted square planar structure in its crystal unit, but with exchangeable pattern, it was found that Zn-complex exhibited the distorted tetrahedral structure. In construct, Ni-complex appeared as a distorted square planar geometry in its modulated X-ray structure like Pd-complex. The electronic transition study investigated that there is some di culty in synthesis of the modulated rst periodic table raw complexes at the same conditions of Pd-synthesis. Molecular docking simulation analysis selected E-coli as the expression system to evaluate the total energy score of the three studied complexes with 1O6S and 2BHM protein targets.

Declarations
Declaration of Competing Interest The author declare that they have no known competing nancial interests or personal relationships that could have appeared to in uence the work reported in this paper.

Funding
No funding applicable for this article Con icts of interest/Competing interests: No potential con ict of interest was reported by the authors Availability of data and material: My manuscript and associated personal data will be shared with Research Square for the delivery of the author dashboard.
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Author contributions: Material preparation, data collection, and analysis, the rst draft of the manuscript was performed and written by Doaa S El-Sayed (modulated structure), with labeled coordinated centers Investigated UV-Vis spectra of the studied complexes using TD-DFT method