IN SILICO STUDIES OF METHYL N-(6-PROPYLSULFANYL-1H-BENZIMIDAZOL-2-YL)CARBAMATE: QUANTUM CHEMICAL ANALYSIS AND MOLECULAR DOCKING STUDY WITH VEGFR-2

ABSTRACT

This study presents a quantum chemical analysis of methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl)carbamate, focusing on its electronic structure, stability, and potential as a coordinating ligand. Using the Restricted Hartree-Fock (RHF) method with the STO-3G basis set, key parameters such as HOMO-LUMO energy levels, electron density, charge distribution, dipole moment, and total energy were determined. This study also investigates the molecular docking of methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl)carbamate with Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2). The results revealed multiple binding poses, with the most stable interaction showing a Vina score of -6.8 kcal/mol, indicating a strong ligand-receptor complex. These findings support methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl)carbamate’s potential role in targeting VEGFR-2-mediated pathways, reinforcing its relevance in cancer research. Moreover, the heteroatom-rich benzimidazole core and carbamate functionality suggest potential metal coordination behavior, highlighting its promise as a candidate ligand in future coordination chemistry applications.

АННОТАЦИЯ

Это исследование представляет собой квантово-химический анализ метил N-(6-пропилсульфанил-1H-бензимидазол-2-ил)карбамата с акцентом на его электронную структуру, стабильность и потенциал в качестве координирующего лиганда. С использованием метода ограниченного Хартри-Фока (RHF) и базиса STO-3G были определены ключевые параметры, такие как уровни энергии HOMO-LUMO, электронная плотность, распределение заряда, дипольный момент и полная энергия. Также в исследовании рассматривается молекулярный докинг метил N-(6-пропилсульфанил-1H-бензимидазол-2-ил)карбамата с рецептором сосудистого эндотелиального фактора роста 2 типа (VEGFR-2). Результаты показали несколько вариантов связывания, при этом наиболее стабильное взаимодействие характеризовалось значением Vina -6.8 ккал/моль, что указывает на прочный комплекс лиганда с рецептором. Полученные данные подтверждают потенциальную роль метил N-(6-пропилсульфанил-1H-бензимидазол-2-ил)карбамата в нацеливании на пути, опосредованные VEGFR-2, подчеркивая его значимость для исследований в области онкологии. Более того, богатое гетероатомами бензимидазольное ядро и функциональность карбамата предполагают потенциальное поведение в координации с металлами, подчеркивая его перспективность в качестве потенциального лиганда в будущих применениях координационной химии.

Keywords: benzimidazole derivatives, HOMO-LUMO gap, electronic properties, dipole moment, charge distribution, molecular orbitals, ligand interactions, VEGFR-2, angiogenesis, anti-cancer activity, ligand-receptor interaction, drug repurposing.

Ключевые слова: производные бензимидазола, энергетический зазор HOMO-LUMO, электронные свойства, дипольный момент, распределение заряда, молекулярные орбитали, взаимодействие лиганда, VEGFR-2, ангиогенез, противораковая активность, взаимодействие лиганд-рецептор, повторное использование лекарств.

INTRODUCTION

The study of benzimidazole derivatives has garnered considerable attention due to their diverse applications in medicinal chemistry and biological systems. These compounds, characterized by their fused benzene and imidazole rings, exhibit a plethora of biological activities, most notably their anticancer properties. Specific structural modifications, such as the addition of substituents like chlorophenyl or piperonyl, have been shown to enhance their cytotoxic effects against various cancer cell lines, including A549 cells, which are a model for lung cancer [1]. Additionally, benzimidazole derivatives possessing thiazole moieties have demonstrated promising anti-HepG2 activity, reinforcing the utility of these compounds in combating hepatocellular carcinoma [2].

Recent quantum chemical studies have illuminated the potential of benzimidazole derivatives as corrosion inhibitors and their inherent molecular stacking interactions. For instance, π-π stacking interactions of these heterocycles can significantly influence their biological activities, including DNA binding and anticancer properties [3]. This has been supported by theoretical studies involving density functional theory (DFT) calculations that examine these interactions [4]. Furthermore, the structural elucidation and characterization of benzimidazole derivatives using analytical techniques like NMR and XRD enhance our understanding of their physicochemical properties, which are crucial for predicting biological outcomes [5].

To optimize the synthesis of benzimidazole derivatives, multiple methodologies have been pursued, including microwave-assisted synthesis and the use of organo-heterogeneous catalysts, enhancing reaction efficiencies and yields. The catalytic properties of montmorillonite K10 have demonstrated effective synthesis routes for producing benzimidazole derivatives with high yields [6]. Additionally, solvent effects have been explored, revealing intrinsic characteristics of solvents that can affect proton transfer dynamics within benzimidazole structures, thus influencing their biological reactivity [7].

Moreover, benzimidazole derivatives have emerged as vital scaffolds in the design of novel anticancer agents, with extensive studies indicating their efficacy in inducing apoptosis in various cancer cell lines [8], [9]. The intricate relationship between structure and biological activity has been explored through structure-activity relationship (SAR) studies, driving the development of new compounds with enhanced therapeutic profiles [10]. For example, derivatives containing specific alkyl chains and cyclic moieties have shown improved cytotoxic effects against breast and ovarian cancer cell lines [8].

Molecular docking studies of benzimidazole derivatives have become increasingly relevant in the context of drug design. Several docking studies have demonstrated that benzimidazole derivatives can serve as effective inhibitors of bacterial DNA gyrase, a crucial enzyme for bacterial DNA replication. This unique targeting is vital since DNA gyrase is present in prokaryotes but absent in higher eukaryotic organisms, thus minimizing the risk of toxicity in human cells. The study by Kashid et al. illustrated that molecular docking against the DNA gyrase subunit b revealed promising binding affinities for various benzimidazole derivatives, supporting their potential as antimicrobial agents [11].

Moreover, the molecular docking of benzimidazole derivatives with dihydropteroate synthase (DHPS) has further reinforced their role as potential antibacterial agents. Salubi’s research highlighted specific binding interactions of benzimidazole compounds with DHPS, establishing key amino acids that constitute the active site, thereby confirming the mechanism of inhibition [12]. Similarly, docking studies against dihydrofolate reductases from pathogenic strains demonstrated high binding affinities, indicating the potential of these compounds to obstruct essential biosynthetic pathways in bacteria [13].

In addition to antibacterial activity, benzimidazole derivatives have been subjected to docking studies related to anticancer properties. Research by Koparde et al. revealed that docking simulations could elucidate interactions of novel benzimidazole derivatives with targets linked to cancerous processes, thereby guiding the design of compounds with improved efficacy against various cancers [14]. These studies often involve assessing binding affinities and conformations that challenge established cancer treatment protocols by targeting specific cancer-related enzymes and receptors.

Interestingly, the structural modifications of benzimidazole derivatives have been evaluated through these docking studies to understand their pharmacokinetic properties as well. For instance, the computational study by Thapa et al. focused on substituted benzimidazoles, correlating specific binding interactions with enhanced therapeutic activity against tuberculosis [15]. Such findings underscore the importance of tailoring molecular structures to optimize biological activity and efficacy.

Furthermore, the implications of these studies extend to identifying the binding mechanisms and predicting the ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles of potential drug candidates. A comprehensive study by Zubrienė et al. noted that benzimidazole-containing compounds exhibit a significant affinity for carbonic anhydrases, showcasing their multidimensional pharmacological potential [16].

MATERIALS AND METHODS

Computational details

Quantum chemical calculations were performed using the Gaussian software package. The molecular geometry of methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl) carbamate was optimized using the Restricted Hartree-Fock (RHF) method in conjunction with the STO-3G basis set. This level of theory was chosen to balance computational cost with sufficient accuracy for qualitative analysis of electronic properties.

Following geometry optimization, key electronic parameters were calculated, including the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) energies. The HOMO-LUMO energy gap (ΔE) was computed as an indicator of molecular reactivity and stability. Additionally, the total electronic energy, molecular dipole moment, and atomic charge distribution were evaluated.

The electron density and electrostatic potential (ESP) maps were generated to visualize regions of high and low electron concentration. These visual representations facilitated identification of nucleophilic sites within the molecule, particularly atoms suitable for coordination with transition metals. Graphical illustrations of the HOMO and LUMO orbitals were prepared to highlight frontier orbital localization. The charge distribution was also visualized. Tabulated data includes total energy, dipole moment, HOMO/LUMO energies, and energy gap values.

Protein and ligand preparation

The three-dimensional structure of the human Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) kinase (PDB ID: 3VHE) was obtained from the Protein Data Bank. The protein structure was pre-processed using PyMOL software by removing intrinsic water molecules from the binding pocket and adding polar hydrogens to improve docking accuracy. Additionally, the structure was checked for missing side-chain residues and corrected using open Molecular Mechanics (MM) simulation tools.

The molecular structure of methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl) carbamate was retrieved from the PubChem database. The ligand geometry was optimized using the AM1 semi-empirical method, and the optimized structure was converted to PDB format for docking studies.

Molecular Docking and Binding Site Analysis

Molecular docking simulations were conducted using AutoDock Vina integrated in AutoDock v4.2.6. A blind docking approach was employed to explore the potential binding poses within the entire VEGFR-2 receptor surface. Docking was performed with a defined grid covering the protein to identify the most favorable binding sites and interactions. Multiple poses were evaluated based on their Vina scores (kcal/mol), cavity volume (ų), and interacting amino acid residues.

Four stable binding poses were identified, with Vina scores ranging from -6.8 to -5.3 kcal/mol. The best binding pose exhibited a Vina score of -6.8 kcal/mol, indicating strong ligand-protein interaction. The coordinates, cavity volumes, and specific amino acid residues involved in binding were recorded for each pose. Binding site residues for the most stable interaction included LEU21, ARG23, VAL25, ALA43, LYS45, GLU58, among others.

RESULTS AND DISCUSSIONS

In figure 1 shown the charge distribution of each atom and total electron density of the compound calculated using the ab initio method.

Figure 1. Graphic representation of charge distribution and total electron density in atoms of methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl) carbamate

As you can see in the figure, the number one and number three nitrogen atoms in benzimidazole ring have the high negative charges. Their values are -0.345 and -0.306 respectively. There is also the carbonyl’s oxygen atom in carbamate group has the highest negative charge within carbamate group, its value is -0.305. Total electron density image also supports this calculation by showing thick orange-red patterns around these atoms which shows the abundance of electron pairs. This property allows the compound to form coordination compounds with transition metals.

Understanding the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) is crucial for analyzing the electronic properties of ligands and coordination compounds. The HOMO represents the highest energy level of electrons that are occupied in a molecule. It is primarily involved in electron donation during chemical reactions. The LUMO is the lowest energy level that can accept electrons. It plays a critical role in electron acceptance processes [17] (Shown in the Figure 2.).

Figure-2 displays a graphical depiction of these values for the methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl) carbamate. Red brown indicates high electron density in the molecular orbital, whereas green indicates low electron density.

Figure 2. Graphical representation of the calculated HOMO and LUMO orbitals of methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl) carbamate

The energy gap between these two orbitals is known as the HOMO-LUMO gap. It refers to the energy difference between the Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO). This gap plays a significant role in determining the electronic, optical, and chemical properties of molecules. A larger HOMO-LUMO gap generally indicates greater stability and lower reactivity of a compound. Conversely, a smaller gap suggests higher reactivity and lower stability [18].

The HOMO was predominantly localized over the benzimidazole moiety and sulfur-containing substituent, suggesting its potential role in electron donation during complex formation. Conversely, the LUMO was primarily situated on the carbamate group, indicating regions where electron acceptance could occur.

Table 1 below presents the calculated values of the HOMO and LUMO orbitals for the compound as well as total energy and dipole moments, utilising quantum chemical calculation methods.

Table 1.

The HOMO and LUMO energies of the compound and the difference between them, as well as the total energy and dipole moment, are given

The quantum chemical calculations provide essential insights into methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl) carbamate’s potential as a ligand in complex formation. The total energy of -1159.726 a.u. reflects the stability of the molecule in its isolated state, which is crucial when considering its behavior in coordination chemistry. The dipole moment of 2.5922 Debye indicates a degree of polarity that may influence its interaction with metal ions, affecting solubility and coordination tendencies. The HOMO energy of -0.7682 eV and LUMO energy of 0.6870 eV result in an energy gap of 1.4552 eV, suggesting a capacity for electronic transitions that could facilitate charge transfer interactions with metal centers. These quantum chemical parameters highlight methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl) carbamate’s electronic structure, reinforcing its potential as a coordinating ligand in metal complex formation.

Methyl N-(6-propylsulfanyl-1h-benzimidazol-2-yl) carbamate, a benzimidazole derivative, primarily exerts its pharmacological effects by binding to β-tubulin, thereby inhibiting microtubule polymerization. This mode of action has been supported by several studies, including one where researchers utilized molecular docking to identify binding sites and affinities of methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl) carbamate and its derivatives against mutant and wild-type tubulin structures. This study indicated that methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl) carbamate possesses a robust binding affinity that varied depending on the mutations present in tubulin [19.].

Additionally, methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl) carbamate has been shown to disrupt microtubule function, causing cytotoxicity in tumor cells, thereby broadening its therapeutic implications to include anti-cancer activity [20.].

Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) plays a pivotal role in tumor angiogenesis, facilitating the formation of new blood vessels that supply nutrients and oxygen to tumors, thereby promoting their growth and potential metastasis. Overexpression of VEGFR-2 has been observed in various cancers, including gastric and ovarian cancers, and is associated with poor prognosis and increased tumor aggressiveness [21].

Table 2.

 Vina scores coordinates, cavity volumes and active binding sites of methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl) carbamate in with VEGFR-2 receptor protein in different poses

In Table 2, we can see that a blind docking analysis was performed using Autodock, in which methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl) carbamate is in four different poses in the protein cavity. The first column of the table presents the Vina scores. The smaller the negative value of the Vina score, the higher the protein-ligand bond strength, and the ligand and protein have a strong interaction in this pose. If we look at the table, we can see that the Vina scores range from -6.8 to -5.3. The smallest Vina score is -6.8, which shows the strongest ligand-protein binding in this pose. The second column of the table presents the coordinates of the ligand in different poses within the protein cavity. The third column presents the volumes of the protein cavity. The fourth column presents the active binding sites of the ligand and the protein amino acids. In Figure 3, we can see the binding of the most stable pose in the protein cavity and the active binding site.

Figure 3. Active binding site of the most stable pose of methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl) carbamate and its view in VEGFR-2 receptor protein cavity

The strong binding affinity observed in the best docking pose supports the potential of methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl) carbamate to interact effectively with VEGFR-2. As VEGFR-2 plays a central role in tumor angiogenesis by promoting endothelial cell proliferation and new blood vessel formation, its inhibition can significantly impair tumor growth and metastasis.

The involvement of critical amino acid residues such as ARG23, LYS45, and GLU58 in the binding interaction indicates that the ligand may interfere with the receptor’s kinase activity, potentially leading to downstream inhibition of angiogenic signaling pathways.

These findings are consistent with previous studies indicating that benzimidazole derivatives, including carbamates, possess cytotoxic properties by targeting tubulin and other cellular structures. The current study extends this understanding by demonstrating that such compounds may also act on receptor tyrosine kinases like VEGFR-2, thereby offering a dual mechanism of anti-cancer action.

Conclusion

The present study integrates quantum chemical analysis and molecular docking to evaluate the structural and biological potential of methyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl) carbamate. Quantum chemical calculations reveal a HOMO-LUMO energy gap of 1.4552 eV and a dipole moment of 2.5922 Debye, indicating moderate chemical reactivity and molecular polarity—factors that may enhance its ability to coordinate with metal centers. Charge distribution analysis further highlights electron-rich donor sites, supporting its potential as a coordinating ligand in transition metal complexes.

Complementary molecular docking studies against VEGFR-2, performed using AutoDock Vina, demonstrate favorable binding interactions, with the most stable pose exhibiting a binding affinity of –6.8 kcal/mol. Key amino acid residues involved in ligand binding include LEU21, ARG23, VAL25, ALA43, LYS45, and GLU58, suggesting potential for VEGFR-2 inhibition. Considering the critical role of VEGFR-2 in tumor angiogenesis, these findings not only underscore the compound’s relevance in coordination chemistry but also highlight its promise as a candidate for anticancer drug development.

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