SPECTROPHOTOMETRIC, QUANTUM CHEMICAL AND MOLECULAR DOCKING INVESTIGATIONS OF 4 H -1-BENZOPYRAN-DERIVED Pd(II) COMPLEXES

. Transition metal complexes are an appealing target in the development of functional materials used frequently in industrial and therapeutic world. The quantum chemical investigations help to obtain a thorough comprehension of the interplay between complexes and biological materials. It necessitates sufficient modeling of chemical phenomena in the system, occasionally involving assistance of classical or semi-empirical computational techniques. Identification of the factors influencing complexes and their optimization is essential for electronic structure calculations and the relevant biochemical potential. The present study aims at correlating analytical studies with the theoretical behavior involving identification of structural features and bonding interactions of the three 4 H -1-benzopyrans and their spectrophotometrically analyzed palladium complexes using DFT calculations to get acquainted with pharmacological profile of the complexes. FMO studies indicated a higher Egap for ligand in all the cases than their respective Pd(II) complexes. Furthermore, according to the other chemical descriptors, interaction between the ligands and respective complexes, cause chromogenic ligand’s chemical hardness to decrease indicating that the formed complexes have lower kinetic stability and more chemical reactivity. Efficiency of the studied ligands further was analyzed by molecular docking against the target proteins, of which 2O0U, a transferase exhibited mutual interactions with all the examined ligands.


INTRODUCTION
In recent decades, there has been a surge of interest in the chemistry of transition elements -a rapidly growing and strategically significant area of study.Due to the elements' wide range of industrial applications as alloying elements and the significance of a few of them, especially platinum group metals (PGMs), in biological systems, there is a great deal of interest in the chemistry of these elements [1].In addition to their inherent significance, these investigations are being propelled more and more by the utilization of transition-metal compounds as solar energy conversion sensitizers [2], phosphorescent dyes for display purposes [3], luminescence-based sensors [4], photocatalyst [5], active elements of electron, photoinitiators [6], electron transfer triggers in biomolecules.Transition metal complexes can be controlled through ligand design and metal selection, exhibiting beautiful colors and rich-excited state behavior.Understanding electronic excited states is crucial in spectroscopic, photophysical, photochemical and theoretical research [7].Although the behaviour of the metal-organic bond can be highly tuned to achieve desired properties, it is difficult to forecast and hence, calls for a thorough search across a large and intricate space to find the right target for desired applications.The efforts have been made to theoretically study this class through the application of quantum chemical methods.It has been established that driving force behind the development of many quantum chemistry approaches is the intrinsic behaviour of the metal atom at its electronic level.
Palladium, one of the transition metals especially PGMs and a relatively rare platinum metal with atomic number 46, has the widest practical application in various industries, making it a valuable resource.Pallas is the name of a small planet that was discovered in 1802, and it is the source of palladium, and hence its name.The majority of the world's supply of the metal originates from ores that are found in the Soviet Union, Canada, and South Africa.Palladium is a lustrous, ductile, silvery-white metal that melts easily.Palladium is a common alloying element utilized in jewellery.Moreover, palladium also serves as a catalyst.The development of new and improved methods for detection and determination based on sensitive and specific reactions of the elements has been greatly sparked by the study of such a wide range of materials containing trace to high concentrations of palladium [8].
Numerous analytical techniques are available for trace and ultra-trace analysis of elemental composition.Atomic absorption spectrometry (AAS) is the most widely used for trace palladium determination in the parts per million concentration range.Ultra trace element determination requires a more sensitive technique, including potentiometry and voltammetry [9], X-ray [10] and nuclear methods [11].Electrochemical methods measure free ions and oxidation states.Atomic spectrometric techniques measure total element content but can be affected by the sample matrix.X-ray and nuclear techniques offer low detection limits and matrix insensitivity.Routinely, the determination of trace metals has been carried out by inductively coupled plasma atomic emission spectrometry [12], inductively coupled plasma mass spectrometry [13] electrothermal atomic absorption spectrometry [14], and flame atomic absorption spectrometry [15].However, there are several drawbacks to the current techniques, such as low sensitivity, a limited pH range, poor temperature control, costly equipment, and large time consumption.Finding an advantageous technique over the limitations of the above-mentioned is highly desirable.Hence, spectrophotometric methods of determination of palladium are mostly preferred as these are costeffective, easy to handle, and rapid processes with comparable sensitivity, selectivity, and accuracy with good precision [16][17][18][19][20][21][22][23][24][25].
Here, our goal is to provide an application of computational chemistry, particularly quantum chemical modeling that has significantly contributed to understanding structure-property relationships and designing inorganic molecules, especially transition metal complexes.Recent advancements in computational chemistry have enabled efficient computation and interpretation of the electronic structures of metal complexes, often based on known structural data.Reliable structure prediction is crucial for predicting molecular properties and designing novel complexes [26].Quantum chemical methodologies [27], particularly density functional theory (DFT) methods [28], are useful for studying chemical reactivity, analyzing complex reactions, and modeling catalytic reactions.Computational chemistry is widely used by theoreticians and experimental catalysis groups, with results often used to support mechanistic proposals.Modern computational approaches have achieved near-chemical accuracy, with the correlation between molecular modeling results and experimental data becoming a common practice [29].
Not only does computational chemistry help in estimating the structural features and bonding interactions of the compounds in chemistry, but it also helps in estimating and analyzing the biochemical activity and binding affinity of the compounds against a biological target by using a computer-assisted molecular docking study.Molecular docking is a perfect technique to be employed in drug development for the industry to reduce synthesis time and cost while increasing medicine efficacy.It is one of the computational procedures that aims at predicting the precise ligand binding site of its target macromolecule (protein receptors) to form a stable complex [30,31].According to Mohapatra et al. [32] first, ligand conformations are sampled according to the protein's active site, and then the conformations are ranked according to a scoring function.
The objectives of this study thus are to highlight the rapid discovery of structure-property relationships in transition-metal chemistry through the integration of computational chemistry and computer science advancements.
The selected ligands were docked with the protein receptor molecules in the functional groups of five different proteins, belonging to the classification transferase (2O0U, 5OMY, 6EQ9, 7ORF) [33][34][35][36] and signaling protein/inhibitor (6P0I) [37] domains, with the help of Chimera 1.14 [38] and Auto Dock-Vina [37] software.The database was acquired from the protein data bank (RCSB PDB) [40] and the Swiss ADME prediction [41] site made predictions for each of the selected proteins.To find the proteins with the best-fit interactions and the lowest binding energy value, several docking runs have been carried out.The molecule's bioactive nature is shown by its lowest binding energy value [42].These sampling algorithms help to identify the most energetically favorable conformations of the ligand within the protein's active site, considering their binding mode.

Optimization of Pd(II)-4H-1-benzopyran complexes
DFT studies revealed that all compounds were associated with the C1 point group.The optimized molecular geometry of all the reagents and their respective Pd(II) complexes is shown in Figure 1, represented by colored atoms and numbering, where red color is for oxygen atom, yellow for sulfur, green for chlorine, grey for carbon, white for hydrogen and greenish blue stands for palladium.
Some of the calculated bond lengths and bond angles for all the compounds shown in Figure 1 have been discussed in Tables 1a and 1b.

Molecular electrostatic potential (MEP)
The MEP analysis gives an idea regarding the distribution of charge across the 3D molecular surface.The colour grading helps in distinguishing the electron-rich surface areas from the electron-deficient ones [43].Various physicochemical properties of the title compounds were analyzed on the basis of MEP studies.Figure 2 shows the MEP surface for HMTB and Pd(II)-HMTB, CHMTB, and Pd(II)-CHMTB, CHMFB, and Pd(II)-CHMFB with color variation induced by the difference in charge density.The decreasing magnitude of the electrostatic potential observed is in the following order: blue, green, yellow, orange and finally red.For the given MEP surface, the highest negative potential had been observed at -  2, the negative electrostatic potential was found over doubly bonded oxygen atoms for HMTB, CHMTB, and CHMFB, whereas it was observed over the hydroxide group bonded with Pd (II) atom for Pd(II)-HMTB, Pd(II)-CHMTB and Pd(II)-CHMFB complexes.On the other hand, the lesser positive electrostatic potential was depicted over the hydrogen atoms bonded to the aryl carbon atoms of the rings.

FMO HOMO-LUMO energy gap
The HOMO to LUMO energy band gap can be used to analyze the compound's stability, chemical activity, and other variables.The chemical reactivity indices like chemical hardness, electronegativity, electronic chemical potential, and electrophilicity index, were calculated for the title compound using the energy values of HOMO and LUMO [45].The various relevant pairs of molecular orbitals along with the energy gap between HOMO and LUMO is 3.56 eV (HMTB), 4.24 eV (CHMTB), 9.71 eV (CHMFC), 1.22 eV (Pd(II)-HMTB), 2.76 eV (Pd(II)-CHMTB) and 2.51 eV (Pd(II)-CHMFC) are as shown in Figure 3, and this is also an important parameter for determining the electron conductivity.Chemical hardness is an indication of the stability and reactivity of a chemical system.This descriptor is used as a measure of resistance to change in the electron distribution or charge for the given molecule.As shown in Table 2, the molecule's chemical hardness was calculated to be 1.78 eV (HMTB), 2.12 eV (CHMTB), 4.86 eV (CHMFB), 0.61 eV [Pd(II)-HMTB complex], 1.38 eV [Pd(II)-CHMTB complex] and 1.26 eV [Pd(II)-CHMFB complex].A reasonably high value indicates the substance is chemically stable or very close to its stability.The electronegativity value, which measures the power of an atom in a molecule to attract electrons towards it was found to be 4.07 eV (HMTB), 4.15 eV (CHMTB), 4.11 eV (CHMFB), 2.9 eV [Pd(II)-HMTB complex], 4.79 eV [Pd(II)-CHMTB complex] and 5.03 eV [Pd(II)-CHMFB complex].The electrophilicity index which measures the ability of a molecular species to soak up electrons was found to be 4.65 eV (HMTB), 4.06 eV (CHMTB), 1.74 eV (CHMFB), 6.89 eV [Pd(II)-HMTB complex], 8.31 eV [Pd(II)-CHMTB complex] and 10.04 eV [Pd(II)-CHMFB complex].The electrophilicity index has also been found to be useful in predicting toxicological behavior.And finally, the computed value for the chemical softness is 0.56 eV (HMTB), 0.47 eV (CHMTB), 0.21 eV (CHMFB), 1.64 eV [Pd(II)-HMTB complex], 0.72 eV [Pd(II)-CHMTB complex] and 0.79 eV [Pd(II)-CHMFB complex] and is thus predicted to have very low toxicity

Molecular docking
Furthermore, using molecular docking against target proteins, the efficiency of the studied ligands was analyzed and discussed.The least binding energies (kcal/mol), H-bond distance, and residue involved in other non-covalent interactions obtained by docking analysis of molecules were represented in tabulated form (Table 3).In all the protein receptors, 2O0U showed the least energy of binding at -8.7 kcal/mol for ligands HMTB (A) and CHMTB (B), whereas -8.1 kcal/mol for CHMFB (C) and this was the most docked proteins among all that interacted with the ligands.2D-plotting of docked complexes for identifying the other non-covalent interactions other than H-bond along with residue involved in it were done by using Biovia discovery studio tool [47].This receptor protein consists of 3 residue and hydrogen bonds possessing H-bond lengths of 2.60 and 2.32 Å for ligands A and B, respectively.All the three compounds A, B and C were found to interact with various different receptors and its other non-covalent interactions were as depicted in Figures 4, 5

CONCLUSION
In coordination compounds, the transition metals have the unusual ability to cause notable alterations in the electronic structure of the ligands involved, frequently resulting in a dramatic alteration in their chemical and biological behavior.This ability helps to explain how they have evolved into living systems.The intricacy of the behaviour of metal atom at the electronic level is the driving force behind the development of many quantum chemistry approaches for their explanation.The present study incorporates a theoretical study with satisfactory results of the 4H-1-benzopyrans exhibiting unique chelating and biological properties towards palladium in its divalent state.The chelating efficacy of the selected bidentate ligands viz.3-hydroxy-2-[2'-(5'methylthienyl)]-4-oxo-4H-1-benzopyran (HMTB), 6-chloro-3-hydroxy-7-methyl-2-(2′-thienyl)-4-oxo-4H-1-benzopyran (CHMTB) and 6-chloro-3-hydroxy-7-methyl-2-(2'-furyl)-4-oxo-4H-1benzopyran (CHMFB) shown by coordinating the 4H-1-benzopyran rings to palladium(II) centers as described in our previous analytical research [21][22][23], when extended to DFT calculations generated the ideal and optimized complex structures.The existence of electron density around the pyran ring in the three mentioned ligands and around the core metal atom in their respective Pd(II) complexes has also been amply demonstrated by the MEP structures both for the ligands and their bivalent metal complexes, supporting the presence of coordinating sites.Although, all the three selected benzopyrans were able to interact with different protein receptors as indicated during molecular docking studies with respect to five variable proteins as 2O0U, 5OMY, 6EQ9, 7ORF and 6P0I belonging to different domains, yet, the protein 2O0U interacted properly with all the three described ligands as is indicated by the least value of binding energy, hence exhibited mutual interactions with all the three examined ligands.

Figure 3 .
Figure 3. Atomic orbital HOMO-LUMO composition of the frontier molecular orbital and energy gap of the studied reagents and corresponding Pd(II) complexes.
, 6 and 7.The least value of binding energy shows that the protein 2O0U is the potentially active compound which properly interacted with all the three described ligands A, B and C.

Figure 5 .
Figure 5. 3D orientations of HMTB [ligand A] in the active site of the selected proteins.

Figure 6 .Figure 7 .
Figure 6.3D orientations of CHMTB [ligand B] in the active site of the selected proteins.

Table 2 .
Calculated energy values of the studied reagents and their palladium(II) complexes.