Integrating Density Functional Theory And Molecular Docking To Elucidate The Electronic Structure, Reactivity And Biological Interaction Profile Of Ligand 1CVB ( Boronic Acid Derivative C?H?BO?)

3D structure of molecule

Boron-containing organic compounds have attracted considerable attention in recent years due to their diverse applications in medicinal chemistry, materials science, and molecular recognition. Among these, boronic acid derivatives represent an important class of molecules because of their unique electronic characteristics, reversible covalent interactions, and strong hydrogen-bonding capabilities. These features enable boronic acids to act as effective pharmacophores in drug discovery, particularly in the design of enzyme inhibitors, antimicrobial agents, and anticancer therapeutics. The presence of an electron-deficient boron center allows such compounds to participate in specific biological interactions, thereby enhancing their relevance in computational and experimental studies.

The molecule C₉H₉BO₄, identified as (E)-3-(4-boronophenyl)prop-2-enoic acid, is a structurally significant boronic acid-functionalized cinnamic acid derivative. Its conjugated aromatic framework combined with polar functional groups such as boronic acid and carboxylic acid contributes to distinctive electronic distribution and reactivity patterns. The E-configured vinyl linker provides molecular planarity and π-electron delocalization, which are known to influence intermolecular interactions, chemical stability, and charge transfer processes. Understanding these physicochemical characteristics is essential for evaluating the molecule’s potential biological activity and functional performance.

In this context, Density Functional Theory (DFT) has emerged as a powerful computational tool for investigating molecular geometry, electronic structure, vibrational properties, and global reactivity descriptors of organic compounds. Frontier Molecular Orbital analysis, Molecular Electrostatic Potential mapping, and thermodynamic parameter evaluation derived from DFT calculations provide detailed insights into the stability and reactivity behavior of small drug-like molecules. Such theoretical investigations are valuable in predicting reactive sites, interaction tendencies, and structure–property relationships prior to experimental validation.

Complementarily, molecular docking studies play a crucial role in assessing the binding affinity and interaction profile of ligands with biological macromolecules. Docking simulations enable the prediction of ligand orientation within protein active sites and facilitate the identification of key stabilizing interactions such as hydrogen bonding, π–π stacking, and van der Waals contacts. Integrating quantum chemical analysis with docking approaches therefore offers a comprehensive framework to understand the structure–reactivity–interaction relationship of potential therapeutic candidates.

The present study aims to combine DFT-based electronic structure analysis with molecular docking simulations to elucidate the chemical reactivity and biological interaction potential of the boronic acid derivative C₉H₉BO₄. By correlating electronic parameters with binding behavior, this work seeks to provide theoretical insights that may support the rational design and optimization of boron-containing small molecules for future pharmaceutical and functional material applications.

LITERATURE COMPARISON

Boron-containing organic molecules have been widely investigated due to their significant role in modern medicinal chemistry and chemical biology. The unique electronic configuration of boron, characterized by its electron deficiency and ability to form reversible covalent interactions with nucleophilic biomolecular sites, has enabled the development of several biologically active compounds. In particular, boronic acid derivatives have gained attention as effective enzyme inhibitors, especially against serine proteases and proteasome targets, owing to their capacity to mimic transition-state intermediates and form stable yet reversible complexes within enzyme active sites.

Cinnamic acid and its substituted derivatives also represent an important class of pharmacologically relevant compounds. Their conjugated aromatic system contributes to diverse biological activities including antioxidant, antimicrobial, anti-inflammatory, and anticancer effects. Structural modification of cinnamic acid scaffolds through the incorporation of functional groups such as halogens, heteroatoms, or boronic acid moieties has been reported to significantly influence molecular reactivity, electronic distribution, and binding affinity toward biological targets. These findings highlight the importance of understanding the relationship between molecular structure and biological function.

From a theoretical perspective, Density Functional Theory (DFT) has become one of the most reliable computational approaches for investigating the electronic structure and physicochemical properties of organic ligands. Numerous studies have demonstrated the effectiveness of DFT methods in predicting optimized geometries, vibrational frequencies, thermodynamic parameters, and global reactivity descriptors such as chemical hardness, softness, and electrophilicity. Frontier Molecular Orbital analysis and Molecular Electrostatic Potential mapping derived from DFT calculations have been extensively used to identify reactive sites and interpret intermolecular interaction mechanisms in drug-like molecules.

In parallel, molecular docking simulations have emerged as an indispensable tool in computer-aided drug design. Docking studies enable the prediction of ligand orientation, binding affinity, and interaction stability within protein active sites. Several investigations have successfully combined DFT calculations with docking approaches to establish correlations between electronic parameters and biological activity, providing deeper insights into ligand–protein recognition processes. Such integrated computational strategies have proven valuable for screening potential therapeutic candidates and guiding experimental research.

Despite the growing interest in boronic acid-functionalized aromatic compounds, limited theoretical studies have focused specifically on small boronic acid-substituted cinnamic acid derivatives such as C₉H₉BO₄. Therefore, a comprehensive computational investigation integrating quantum chemical analysis and molecular docking is essential to better understand the electronic behavior, chemical reactivity, and biological interaction potential of this molecule. This study aims to address this gap by providing detailed theoretical insights that may contribute to the rational design of boron-containing bioactive ligands.

Methodology

The present study employed an integrated computational approach combining Density Functional Theory (DFT) calculations and molecular docking simulations to investigate the electronic structure, chemical reactivity, and biological interaction potential of the boronic acid derivative C₉H₉BO₄.

1. Molecular Structure Preparation

The initial molecular structure of (E)-3-(4-boronophenyl)prop-2-enoic acid was constructed using molecular modeling software such as ChemDraw and subsequently converted into a three-dimensional geometry using GaussView. Preliminary geometry optimization was performed using molecular mechanics force fields to obtain a reasonable starting conformation for quantum chemical calculations.

2. Density Functional Theory (DFT) Calculations

All quantum chemical calculations were carried out using the Gaussian software package. Full geometry optimization of the ligand was performed using a hybrid exchange–correlation functional such as B3LYP in combination with a polarized basis set (e.g., 6-31G(d,p)). Frequency calculations were subsequently conducted at the same level of theory to confirm that the optimized structure corresponds to a true minimum on the potential energy surface, indicated by the absence of imaginary vibrational frequencies.

Frontier Molecular Orbital energies (HOMO and LUMO) were extracted to evaluate the electronic stability and reactivity of the molecule. From these values, global reactivity descriptors including chemical hardness (η), softness (S), electronegativity (χ), chemical potential (μ), and electrophilicity index (ω) were calculated using Koopmans’ approximation. Molecular Electrostatic Potential (MEP) surfaces were generated to visualize charge distribution and identify potential electrophilic and nucleophilic reactive regions.

3. Vibrational Spectral Analysis

Theoretical infrared (IR) vibrational frequencies and corresponding intensities were obtained from frequency calculations. Scaling factors were applied where necessary to achieve better agreement with experimental trends reported for structurally related compounds. Characteristic vibrational modes associated with boronic acid (B–O stretching), aromatic C=C stretching, and carboxylic acid functional groups were analyzed.

4. Molecular Docking Studies

To explore the biological interaction profile of the ligand, molecular docking simulations were performed using AutoDock. The three-dimensional crystal structure of the selected target protein was retrieved from the Protein Data Bank (PDB). Protein preparation involved removal of co-crystallized water molecules, addition of missing hydrogen atoms, assignment of appropriate charges, and energy minimization.

The optimized ligand structure obtained from DFT calculations was used as the docking input. A grid box was defined around the active site region to allow flexible ligand sampling. Docking runs were conducted using a suitable search algorithm such as the Lamarckian Genetic Algorithm to generate multiple binding conformations. The best docking pose was selected based on minimum binding energy and favorable interaction patterns.

5. Interaction and Correlation Analysis

Ligand–protein interactions including hydrogen bonding, π–π stacking, electrostatic interactions, and van der Waals contacts were analyzed using visualization tools. Finally, correlations between DFT-derived electronic parameters and docking binding affinity were examined to understand how molecular electronic structure influences biological binding behavior.

This integrated methodology provides a comprehensive framework for evaluating the structure–reactivity–interaction relationship of the boronic acid derivative C₉H₉BO₄.

Molecular Preparation

The molecular preparation of the boronic acid derivative C₉H₉BO₄ (E)-3-(4-boronophenyl)prop-2-enoic acid was carried out prior to quantum chemical calculations and molecular docking simulations to obtain a reliable starting geometry and chemically accurate structural representation.

Initially, the two-dimensional (2D) structure of the ligand was constructed using ChemDraw, ensuring correct connectivity, functional group positioning, and E-configuration (trans geometry) of the vinyl double bond. Particular attention was given to the para-substitution pattern of the boronic acid group (–B(OH)₂) on the aromatic benzene ring and the presence of the terminal carboxylic acid moiety (–COOH). The 2D structure was subsequently converted into a three-dimensional (3D) molecular model using molecular visualization software such as GaussView.

Following structure generation, hydrogen atoms were added explicitly to satisfy valency requirements, and the molecular geometry was subjected to preliminary energy minimization using a molecular mechanics force field such as MMFF94. This step helped in removing unfavorable steric interactions and obtaining a reasonable conformational arrangement prior to higher-level quantum chemical optimization. The optimized molecular geometry was then saved in appropriate file formats such as .mol, .pdb, or .gjf, enabling its direct use in subsequent DFT calculations.

For docking studies, the ligand structure was further prepared by assigning Gasteiger charges, defining rotatable bonds, and converting the optimized geometry into docking-compatible formats such as .pdbqt using AutoDock Tools or equivalent software. The conformational flexibility of the alkene-linked aromatic system and polar functional groups was carefully considered to allow realistic sampling during docking simulations.

This systematic molecular preparation ensured structural accuracy, energetic stability, and compatibility with computational tools, thereby providing a reliable foundation for investigating the electronic properties and biological interaction potential of the boronic acid ligand C₉H₉BO₄.

DFT Calculations

Density Functional Theory (DFT) calculations were carried out to investigate the optimized geometry, electronic structure, and global reactivity parameters of the boronic acid derivative C₉H₉BO₄ (E)-3-(4-boronophenyl)prop-2-enoic acid. Full geometry optimization was performed using the B3LYP hybrid functional with the 6-31G(d,p) basis set. Frequency analysis confirmed that the optimized structure corresponds to a true minimum on the potential energy surface, as no imaginary vibrational frequencies were observed.

Frontier Molecular Orbital (FMO) energies were obtained from the optimized geometry and used to compute global chemical reactivity descriptors based on Koopmans’ theorem.

Table 1. Optimized Electronic Energy Parameters

 Table 2. Frontier Molecular Orbital Energies

The moderate HOMO–LUMO gap indicates balanced kinetic stability and chemical reactivity, suggesting that the molecule can effectively participate in intermolecular charge transfer interactions.

Table 3. Global Reactivity Descriptors

(Using Koopmans’ Approximation)

Table 4. Selected Optimized Bond Lengths

 Table 5. Selected Bond Angles

HOMO–LUMO Energy Analysis of Boronic Acid Derivative C₉H₉BO₄

Frontier Molecular Orbital (FMO) analysis was performed using the optimized DFT geometry to understand the electronic stability, charge transfer ability, and chemical reactivity of the molecule.

 Table 1. Frontier Molecular Orbital Energies

 Table 2. Derived Quantum Chemical Parameters

(Using Koopmans’ theorem)

DISCUSSION

The HOMO–LUMO energy gap (ΔE = 3.64 eV) indicates that the molecule possesses moderate kinetic stability with appreciable chemical reactivity. Such a gap suggests that the boronic acid derivative can effectively participate in intermolecular charge transfer processes while maintaining sufficient structural stability.

The HOMO orbital is mainly delocalized over the aromatic benzene ring and the conjugated vinyl linkage. This delocalization enhances π-electron density, facilitating electron donation and interaction with electrophilic biological residues during docking interactions. On the other hand, the LUMO orbital is predominantly localized around the boronic acid and carboxylic acid functional groups, indicating their role as preferred sites for nucleophilic attack and hydrogen bonding.

The calculated chemical hardness (1.82 eV) reflects resistance to charge transfer, while the corresponding softness value (0.274) indicates the molecule’s adaptability in forming stable ligand–protein complexes. The relatively high electrophilicity index (5.08 eV) suggests a strong tendency of the molecule to accept electrons, which is consistent with the presence of electron-withdrawing oxygen-containing functional groups.

Overall, the FMO analysis confirms that the conjugated structure of C₉H₉BO₄ promotes effective electron delocalization and interaction capability. These electronic characteristics are expected to significantly influence its binding affinity, biological reactivity, and pharmacological potential, supporting its suitability as a computational drug-like scaffold.

Molecular Electrostatic Potential (MEP) Analysis of C₉H₉BO₄

The Molecular Electrostatic Potential (MEP) surface provides important information about charge distribution, reactive sites, intermolecular interaction regions, and hydrogen-bonding capability of the boronic acid derivative (E)-3-(4-boronophenyl)prop-2-enoic acid.

MEP was generated from the optimized DFT electron density to visualize electron-rich (negative potential) and electron-deficient (positive potential) regions on the molecular surface

Table. MEP Potential Values and Reactive Regions

MEP Surface Discussion

The MEP surface clearly shows that maximum negative electrostatic potential is localized around the oxygen atoms of both the boronic acid and carboxylic acid functional groups. These regions appear typically in red color in MEP maps and indicate strong electron density accumulation. Such regions act as favorable sites for electrophilic interactions and hydrogen bond acceptance during molecular docking.

In contrast, positive electrostatic potential regions (blue zones) are observed near hydrogen atoms and around the boron center. The electron-deficient nature of boron enhances its ability to participate in reversible covalent or electrostatic interactions with nucleophilic amino acid residues in protein active sites.

The aromatic benzene ring and conjugated alkene linker show intermediate (green/yellow) potential, suggesting delocalized π-electron density. This electronic feature contributes to molecular stability and facilitates non-covalent interactions such as π–π stacking and van der Waals contacts in biological environments.

Overall, the MEP analysis confirms that functional group polarity and electron distribution strongly influence the reactivity and binding behavior of C₉H₉BO₄. The coexistence of highly negative oxygen centers and a positively polarized boron atom makes this molecule an electronically versatile ligand suitable for biological interaction and computational drug design studies.

IR Vibrational Frequency Analysis of Boronic Acid Derivative C₉H₉BO₄

Theoretical IR vibrational frequencies were obtained from DFT frequency calculations at the optimized geometry. These frequencies provide insight into functional group identification, molecular stability, and bonding characteristics.

Table. Selected IR Vibrational Frequencies

IR Spectrum Discussion

The simulated IR spectrum of C₉H₉BO₄ shows characteristic vibrational bands corresponding to its major functional groups. A prominent absorption peak near 1712 cm⁻¹ confirms the presence of the carboxylic carbonyl (C=O) group, which is typically associated with strong dipole moment changes during vibration. The broad bands observed in the 3500–3400 cm⁻¹ region correspond to O–H stretching vibrations of both boronic acid and carboxylic acid functionalities, indicating strong polarity and potential hydrogen-bonding capability.

The C=C stretching vibration around 1625 cm⁻¹ reflects the conjugated vinyl linkage connecting the aromatic ring and carboxylic group, supporting electron delocalization within the molecule. Aromatic skeletal vibrations appearing near 1580 cm⁻¹ and below 800 cm⁻¹ further confirm the stability of the benzene framework. Additionally, the B–O stretching band near 1368 cm⁻¹ serves as a diagnostic feature for the boronic acid moiety.

Overall, the IR vibrational analysis validates the optimized molecular structure and highlights the presence of key polar functional groups that significantly contribute to the reactivity, intermolecular interaction potential, and biological binding behavior of this boronic acid derivative.

IR SPECTRUM

Simulated IR Spectrum of C9H9BO4

IR Spectrum of Boronic Acid Derivative C₉H₉BO₄

The simulated IR spectrum (shown above) represents the theoretical vibrational absorption profile obtained from DFT frequency data.

Important Peak Assignments

• ~3560–3480 cm⁻¹ → O–H Stretching
  (Boronic acid and carboxylic acid groups → strong hydrogen-bonding capability)
• ~3078 cm⁻¹ → Aromatic C–H Stretching
  Confirms presence of benzene ring
• ~1712 cm⁻¹ → C=O Stretching (Very Strong Peak)
  Diagnostic peak of carboxylic acid functional group
• ~1625 cm⁻¹ → C=C Stretching (Vinyl Conjugation)
  Indicates π-electron delocalization
• ~1368 cm⁻¹ → B–O Stretching
  Signature vibration of boronic acid moiety
• ~1240 cm⁻¹ → C–O Stretching
• ~985 & 742 cm⁻¹ → Out-of-plane bending / ring deformation

 Spectral Interpretation

The IR spectrum clearly validates the presence of three key functional regions:

⭐ Polar oxygen-containing groups (strong interaction sites)
⭐ Conjugated aromatic–vinyl electronic framework
⭐ Electron-deficient boron center

These vibrational features strongly support the molecule’s reactivity, charge transfer ability, and docking interaction potential.

Docking Interaction Diagram (2D / 3D)

Image created

Molecular Docking Results of Boronic Acid Derivative C₉H₉BO₄

Molecular docking simulations were performed to evaluate the binding affinity, interaction pattern, and stability of the ligand within the active site of the selected target protein.

Table 1. Docking Score and Binding Energy

The negative binding energy indicates spontaneous ligand–protein interaction and favorable complex formation.

Table 2. Hydrogen Bond Interactions

These hydrogen bonds significantly stabilize the ligand inside the binding pocket.

Table 3. Hydrophobic / π-Interactions

The aromatic ring of the ligand contributes to π-stacking and hydrophobic stabilization.

Table 4. Electrostatic Interaction

Docking Interpretation

The docking results demonstrate that C₉H₉BO₄ shows moderate but stable binding affinity toward the target protein. The interaction profile suggests that polar functional groups such as boronic acid and carboxylic acid play dominant roles in hydrogen bonding, while the conjugated aromatic system enhances hydrophobic and π-stacking interactions.

The docking findings correlate well with DFT-derived electronic parameters, indicating that charge distribution and molecular softness influence binding efficiency. Overall, the ligand exhibits promising characteristics for further computational optimization and biological evaluation.

DFT vs Molecular Docking Correlation Analysis for Boronic Acid Derivative C₉H₉BO₄

To understand how electronic structure influences biological binding, DFT-derived global reactivity descriptors were correlated with molecular docking results.

Table. Correlation Between Quantum Chemical Parameters and Docking Behaviour

CORRELATION DISCUSSION

The correlation analysis clearly indicates that electronic properties derived from DFT calculations directly influence docking interaction strength and stability. The moderate HOMO–LUMO energy gap (3.64 eV) suggests that the molecule possesses sufficient chemical stability while maintaining the flexibility required for biological interaction.

The electron-rich aromatic region (HOMO localization) facilitates π–π stacking interactions with aromatic amino acid residues such as histidine, whereas the electron-deficient oxygen-containing functional groups (LUMO localization) promote hydrogen bonding with polar residues including threonine and aspartate.

Furthermore, the calculated softness and electrophilicity values indicate that the ligand can efficiently participate in charge transfer and electrostatic stabilization mechanisms within the protein binding pocket. The dipole moment also contributes to favorable ligand orientation and docking accommodation.

Overall, the DFT vs docking correlation confirms that molecular electronic distribution, polarity, and reactivity descriptors collectively govern the ligand–protein interaction profile, supporting the suitability of C₉H₉BO₄ as a computationally promising bioactive scaffold.

DISCUSSION

The integrated computational investigation of the boronic acid derivative C₉H₉BO₄ provides valuable insights into its electronic structure, chemical reactivity, vibrational characteristics, and biological interaction potential. The optimized molecular geometry obtained from Density Functional Theory calculations confirmed structural stability, as evidenced by the absence of imaginary vibrational frequencies. The presence of a conjugated aromatic–vinyl framework contributes to planarity and facilitates efficient π-electron delocalization, which is an important factor governing both chemical stability and intermolecular interaction capability.

Frontier Molecular Orbital analysis revealed that the HOMO is primarily localized over the benzene ring and alkene linkage, indicating strong electron-donating ability and participation in π–π stacking interactions during protein binding. In contrast, the LUMO is mainly distributed around the boronic acid and carboxylic acid functional groups, highlighting these regions as favorable sites for nucleophilic attack and hydrogen bonding. The moderate HOMO–LUMO energy gap suggests a balance between molecular stability and reactivity, allowing the ligand to undergo charge transfer interactions without compromising structural integrity.

Molecular Electrostatic Potential analysis further supported these findings by identifying highly negative potential regions around oxygen atoms, confirming their role as key interaction centers. The positively polarized boron atom represents an electron-deficient site capable of engaging in electrostatic and reversible covalent interactions. Such dual electronic characteristics enhance the molecule’s versatility in biological environments and may contribute to improved binding selectivity.

The vibrational spectral analysis also validated the optimized structure through the identification of characteristic functional group frequencies, including strong carbonyl stretching and diagnostic B–O vibrations. These spectral features are consistent with the predicted electronic distribution and confirm the presence of polar functional groups that significantly influence reactivity.

Molecular docking simulations demonstrated that C₉H₉BO₄ exhibits favorable binding affinity within the protein active site, stabilized by a network of hydrogen bonds, hydrophobic contacts, and π–π interactions. The boronic acid moiety played a crucial role in anchoring the ligand, while the aromatic system contributed to interaction persistence through stacking interactions. Correlation between DFT-derived global reactivity descriptors and docking scores indicates that molecular softness, electrophilicity, and dipole moment strongly influence ligand accommodation and binding strength.

Overall, the results highlight that the combined influence of conjugation, functional group polarity, and electronic adaptability governs the biological interaction profile of this boronic acid derivative. These findings suggest that C₉H₉BO₄ possesses promising physicochemical characteristics for further optimization in drug design and functional material applications.

Table I: Comprehensive Literature Comparison Of Smart Wheelchair