In Silico Exploration of Phytoconstituents and Identification of Hits Against α-Amylase for Antidiabetic Potential

Supriya C. Patil^1,2*, Suresh G. Killedar³, Harinath N. More¹, Ashok A. Hajare⁴, A. S. Manjappa²

¹Bharati Vidyapeeth College of Pharmacy, Kolhapur 416013, Maharashtra, India.

²Vasantidevi Patil Institute of Pharmacy, Kodoli 416114, Maharashtra, India.

³Anandi Pharmacy College, Kalambetarf kale, 416 205, Maharashtra, India.

⁴Bharati Vidyapeeth College of Pharmacy, Palus 416310, Maharashtra, India.

*Corresponding Author E-mail: supriyapatil4063@gmail.com

ABSTRACT:

In the pursuit of effective diabetes management, inhibiting α-amylase activity stands as a critical strategy. This inhibition regulates post-meal blood sugar levels by retarding carbohydrate digestion, mitigating abrupt glucose spikes, and enhancing glycemic control, thus safeguarding against diabetic complications. In this study, molecular docking and DFT investigations were conducted on phytochemical compounds sourced from various plants, unveiling Conanine, Friedelin, Sennoside A, and Sennoside B as promising candidates. These compounds demonstrated robust binding affinities exceeding -9 kcal/mol when targeted against α-amylase, with Conanine leading the charge at -9.5 kcal/mol. Sennoside A and Sennoside B exhibited their effectiveness by forming multiple hydrogen bonds with the enzyme, underlining their strong binding interactions. Furthermore, DFT calculations affirmed the favorable chemical reactivity profiles of these ligands, characterized by significant HOMO-LUMO energy gaps. This research offers valuable insights into potential therapeutic agents for diabetes management, promising better glycemic control and a brighter future for individuals with diabetes.

KEYWORDS: Density Functional Theory, Diabetes, In silico, Molecular Docking, Phytoconstituents.

1. INTRODUCTION: 

Diabetes mellitus has emerged as a pervasive and pressing global health challenge. This pathological condition arises from dysregulation in glucose metabolism, culminating in sustained elevation of blood glucose levels, thereby instigating a state of glucotoxicity¹. Manifesting as a significant contributor to both morbidity and mortality, diabetes exerts its impact across the spectrum of developed and developing nations, poised to ascend to the seventh position among leading causes of mortality by 2030². The prevalence of diabetes burgeoned to encompass approximately 463 million individuals aged 18 to 99 worldwide in 2019, a tally projected to surge to 700 million by 2045³.

Rooted in intricate physiological mechanisms, diabetes stands as a formidable non-communicable disorder and chronic ailment, arising from either insufficient pancreatic insulin secretion or the impaired utilization of endogenously produced insulin⁴. The prevailing landscape characterized by a notable escalation in diabetic incidence finds its nexus in demographic aging, sedentary paradigms, urbanized lifestyles, calorically dense dietary patterns, and the burgeoning specter of obesity, synergistically fomenting a discernible uptick in caseloads over the preceding triennium⁵. In tandem with chronic hyperglycemia, diabetes engenders heightened oxidative stress, perturbing the homeostasis of antioxidant defense mechanisms and fostering a milieu conducive to free radical generation⁶. The utilization of natural products as adjunct therapeutic agents is gaining widespread recognition, driven by their perceived efficacy and a growing body of research highlighting their applicability in the management of diabetes. This trend is spurred by the adverse effects and cost implications associated with conventional diabetes medications⁷. A notable avenue of investigation involves the inhibition of pivotal diabetes-associated enzymes, namely alpha-glucosidase and alpha-amylase, with a view to mitigating hyperglycemia through the orchestrated interplay of antioxidants, such as acetylcysteine, vitamin C, and alpha-lipoic acid, among others. Against this backdrop, our study endeavors to leverage the historical utilization of a plant with established antecedents in diabetes management, aiming to contribute to the global armamentarium against diabetes and its attendant complications⁸. Although a substantial repository of scientific inquiry identifies over 400 plant species exhibiting hypoglycemic attributes, the pursuit of novel anti-diabetic agents drawn from botanical sources continues to captivate scientific interest. This fascination is rooted in the diverse spectrum of phytoconstituents harbored by herbal entities, which possess the potential to serve as efficacious remedies for diabetes. In this milieu, the identification of the most potent pharmacologically active components assumes paramount importance, aligning with the overarching goal of devising a definitive therapeutic regimen for efficacious diabetes management⁹.

Within the expansive purview of botanical medicinals displaying antidiabetic efficacy, select species stand as exemplars. Berberisaristata, an esteemed constituent of traditional systems such as Unani medicine, garnered attention through ethanolic extracts of its root and stem bark evincing noteworthy antidiabetic attributes during glucose tolerance assessments¹⁰. Notably, the root extract of Berberisaristata unveiled berberine as a pivotal component, exerting substantial inhibition against alloxan-induced diabetes progression¹¹. Picrorhizakurroa, acknowledged as kutki within Ayurvedic traditions, occupies a significant niche owing to its multifaceted rhizome extract actions encompassing antidiabetic, antibacterial, antioxidant, anticancer, anti-inflammatory, and hepatoprotective facets¹². Picrorhizakurroa assumes a distinctive role in augmenting blood glucose utilization and absorption, underscored by its potency in orchestrating beta-cell restoration, heightened insulin production, and manifest antihyperglycemic effects¹³. Boerhaaviadiffusa, an herbaceous entity steeped in indigenous, Ayurvedic, and Unani medical legacies, derives therapeutic significance from its diverse chemical reservoir. Its entirety houses compounds endowing exceptional beneficial attributes ¹⁴. The potential of Boerhaaviadiffusa leaf extract to attenuate blood glucose levels is linked with its adeptness in fostering pancreatic beta cell regeneration, substantiating its pronounced antidiabetic potency¹⁵. Pterocarpus marsupium, a salient medicinal presence in traditional practices, notably Ayurveda, merits recognition for its laxative and therapeutic attributes¹⁶. The heartwood extracts of Pterocarpus marsupium harbor pterostilbene, a bioactive agent manifesting promise in type 1 diabetes, insulin resistance, and type 2 diabetes interventions¹⁷. Holarrhenaantidysenterica's aqueous seed extract exhibited salutary effects on blood glucose levels, serum lipids, and body weight, thus emerging as a potential candidate for antidiabetic intervention and amelioration of associated complications¹⁸. Within the Indian context, the use of Eugenia jambolana kernels in decoctions for diabetes management constitutes a common folk practice, representing a key ingredient in diverse diabetes herbal formulations¹⁹. Cassia angustifolia root-derived phytochemicals showcase antidiabetic potential through their affinity for alpha-amylase binding²⁰. Rubiacordifolia, a medicinal entity of substantive scientific import, harnesses the therapeutic utility of its leaves in diabetes management²¹. Intrinsically woven into the fabric of therapeutic options, herbal medicine emerges as a potent armamentarium with a promising trajectory for diabetes treatment²².

2. COMPUTATIONAL METHODS:

2.1 Ligand selection and preparation:

The chemical structures of previously documented phytochemical compounds sourced from Berberisaristata, Picrorhizakurroa, Boerhaaviadiffusa, Pterocarpus marsupium, Holarrhennaantidysentrica, Eugenia jambolana, Cassia angustifolia, and Rubiacordifolia were retrieved from the PubChem database. Subsequently, these downloaded structures underwent energy minimization (EM) utilizing the MMFF94 force field and the steepest descent algorithm. The EM and optimization processes for the selected structures were performed using the PyRx 0.8 software module with the OpenBabel toolkit²³. The optimized ligand structures were subsequently converted into the AutoDockpdbqt format, rendering them suitable for subsequent in-silico investigations.

2.2. Molecular docking study:

The 3D crystal structure of α-amylase (PDB 4W93) was obtained from the RCSB Protein Data Bank. Subsequently, the retrieved protein structures underwent pre-processing steps. First, all previously bound heteroatoms and water molecules were removed. Next, polar hydrogen atoms were systematically added to the refined protein structure to ensure the accurate representation of residue tautomeric states²⁴. The complete protein refinement process was conducted using BIOVIA Discovery Studio²⁵. The processed protein structure was then subjected to an EM step to prepare it for conversion into the AutoDock macromolecule format. Subsequently, molecular docking analyses were carried out utilizing the AutoDockVina module within PyRx 0.8^26–28. During the docking setup, both the refined ligand and protein structures were specified within the Vina Wizard. To encompass the entire protein structure, an appropriately sized grid box was defined within the Vina workspace to facilitate the blind docking study. The exploration of ligand conformational states involved specifying the number of runs, determined by the exhaustiveness parameter, which was set to its default value of eight ^24,29. For each ligand, the docked conformation exhibiting the most negative binding affinity was preserved. Subsequently, binding interactions between the ligands and the target proteins were visualized using BIOVIA Discovery Studio.

2.3. DFT study:

DFT calculations were executed to ascertain frontier molecular orbitals (FMO) and assess the chemical as well as global reactivity descriptors of specific indole alkaloids. The DFT calculations followed established protocols³⁰, employing Orca 4.2.1 software with the B3LYP functional and def2-SVP basis set³¹. Orca-enhanced Avogadro was employed for both input file preparation and output file interpretation. Reactivity descriptors were computed in accordance with Koopmans' theory equations^32–34.

3. RESULTS AND DISCUSSION:

3.1 MOLECULAR DOCKING STUDY:

In this study, conducted a comprehensive molecular docking analysis to ascertain the binding potential of selected ligands sourced from phytochemical origins with respect to a specific target protein. The selection of ligands was based on their relevance to the biological system under investigation, taking into consideration their natural sources and previously reported bioactivities. The goal of molecular docking was to elucidate the binding affinities of these ligands towards the target protein and, subsequently, to identify potential lead compounds. The molecular docking was executed using AutoDockVina, employing the crystallographic structure of the α-amylase (PDB 4W93). Prior to docking, the receptor protein underwent rigorous pre-processing to ensure structural integrity and optimal compatibility with the ligands. Binding affinities were calculated using the Vina scoring function, which takes into account both the intermolecular interactions and the conformational energy of the ligand-protein complex. This scoring function provides a quantitative measure of the binding strength, represented as negative values, where lower scores indicate higher binding affinity. The results of molecular docking analysis have unveiled four promising ligands - Conanine, Friedelin, Sennoside A, and Sennoside B - which have exhibited remarkable binding affinities, each with greater than the -9kcal/mol threshold. These ligands are now poised as prime candidates warranting in-depth exploration and further investigation. Conanine, in particular, has demonstrated a striking binding affinity of -9.9kcal/mol in its interaction with the target α-amylase, as illustrated by the crystallographic structure PDB 4W93. The binding interactions, essential for its high affinity, are thoughtfully depicted in Figure 1, while a comprehensive summary of these interactions is presented in Table 1. Similarly, Friedelin has exhibited a substantial binding affinity of -9.7kcal/mol when engaged with the targeted protein structure. As with Conanine, the binding interactions for Friedelin are visually elucidated in Figure 1, and a detailed summary can be found in Table 1. Sennoside A, another notable ligand, has showcased a significant binding affinity of -9.6kcal/mol. This ligand has formed a remarkable array of interactions, including eight hydrogen bonds, five of which are conventional hydrogen bonds with key residues such as Asp300, Gln63, Thr163, Val354, and Asp356. Additionally, Sennoside A has engaged in two carbon-hydrogen bonds with Gly104 and His305, along with a Pi-donor hydrogen bond with Asp356 as shown in Figure 2. Lastly, Sennoside B has exhibited a commendable binding affinity of -9.6kcal/mol. Its interactions involve the formation of four conventional hydrogen bonds with vital residues including Gln63, Asp353, Asp356, and Val354. Furthermore, Sennoside B has engaged in two carbon-hydrogen bonds with Val354 and Asp356 as shown in Figure 2. These results underscore the potential of Conanine, Friedelin, Sennoside A, and Sennoside B as lead compounds in the pursuit of novel therapeutics. Their robust binding affinities and intricate interactions with the target protein signify their candidacy for further experimental validation and development in the quest to address specific biological pathways and potentially enhance our understanding of α-amylase inhibition.

Figure 1: 2D and 3D binding interaction between docked protein-ligand complexes.

Figure 2: 2D and 3D binding interaction between docked protein-ligand complexes.

Table 1: Binding affinity and interactions of the docked phytochemicals against Human pancreatic α-amylase.

Code	Binding affinity (kcal/mol)	Interacting residues	Type of interaction	Distance
Conanine	-9.9	Tyr62	Pi-Alkyl	5.25
		Trp58	Pi-Alkyl	5.41
		Trp59	Pi-Alkyl	4.13,5.18
Friedelin	-9.7	Trp59	Pi-Sigma	3.98
		Tyr62	Pi-Sigma	3.93
Sennoside A	-9.6	Asp300	Conventional Hydrogen Bond	2.91
		Gln63	Conventional Hydrogen Bond	3.13
		Thr163	Conventional Hydrogen Bond	1.91
		Val354	Conventional Hydrogen Bond	2.08
		Asp356	Conventional Hydrogen Bond	3.06,3.02
		Gly104	C-H Bond	3.27
		His305	C-H Bond	2.52
		Asp356	Pi-Donor Hydrogen Bond	3.46
		His305	Pi-Pi Stacked	2.52
		Trp-59	Pi-Pi T-Shaped	4.33
		Trp59	Pi-Alkyl	5.75
Sennoside B	-9.6	Gln63	Conventional Hydrogen Bond	2.87,3.15
		Val354	Conventional Hydrogen Bond	2.20
		Asp353	Conventional Hydrogen Bond	2.47
		Asp356	Conventional Hydrogen Bond	2.70,2.56
		Val354	C-H Bond	3.33
		Asp356	C-H Bond	3.46
		Trp59	Pi-Pi Stacked	4.63
		His305	Pi-Pi T-Shaped	5.02
		Trp59	Pi-Alkyl	5.74
Rutin	-8.9	Asp300	Conventional Hydrogen Bond	2.31
		Glu233	Conventional Hydrogen Bond	2.21,2.40
		Gln63	Conventional Hydrogen Bond	3.31
		Trp59	Conventional Hydrogen Bond	1.92
		His305	Conventional Hydrogen Bond	1.97
		Asp300	C-H Bond	3.39
		His305	Pi-Sigma	3.98
		Trp59	Pi-Pi Stacked	4.66
		Trp59	Pi-Pi T-Shaped	4.97
		Leu165	Pi-Alkyl	5.10
Quercetin	-8.9	Glu233	Conventional Hydrogen Bond	5.31
		Asp197	Conventional Hydrogen Bond	2.82
		Gln63	Conventional Hydrogen Bond	2.86
		Tyr62	Pi-Pi Stacked	4.25
		Trp59	Pi-Pi Stacked	4.87,4.28
Stigmasterol	-8.9	Lys200	Conventional Hydrogen Bond	3.08
		Tyr62	Pi-Sigma	3.52
		Tyr62	Alkyl	5.41
		His299	Alkyl	4.93
		His201	Pi-Alkyl	5.26
		Lys200	Pi-Alkyl	4.91
		Ile235	Pi-Alkyl	3.91,4.75
Boeravinone B	-8.8	Asp197	Conventional Hydrogen Bond	2.17
		Tyr151	Pi-Donor Hydrogen Bond	4.10
		Leu162	Pi-Sigma	3.67
		Ile235	Pi-Sigma	3.94
		His201	Pi-Pi Stacked	4.92
		Lys200	Pi-Pi T-Shaped	5.32
		Ala198	Pi-Alkyl	4.60,4.75
		Leu162	Pi-Alkyl	4.97
Isoquercetin	-8.8	Ser3	Conventional Hydrogen Bond	2.31
		Thr6	Conventional Hydrogen Bond	2.79
		Arg421	Conventional Hydrogen Bond	2.80,5.98
		Arg398	Conventional Hydrogen Bond	2.97
		Ser289	Conventional Hydrogen Bond	2.27,2.68
		Asp402	C-H Bond	3.43
		Arg252	Pi-Cation	3.87
		Pro4	Pi-Alkyl	4.06,4.87
Liquiritigenin	-8.5	Trp59	Pi-Pi Stacked	4.87,4.28
		Tyr62	Pi-Pi Stacked	4.18
		Trp59	Pi-Pi Stacked	4.21
Kaempferol	-8.5	Asp197	Conventional Hydrogen Bond	1.92
		Tyr62	Conventional Hydrogen Bond	2.89
		Gln63	Conventional Hydrogen Bond	3.06
		Asp197	Pi-Anion	4.93
		Tyr62	Pi-Pi Stacked	2.89
		Trp59	Pi-Pi Stacked	4.31,5.26
Epicatechin	-8.5	Asp197	Conventional Hydrogen Bond	2.10
		Gln63	Conventional Hydrogen Bond	3.17
		Tyr62	Pi-Donor Hydrogen Bond	2.95
		Tyr62	Pi-Pi Stacked	4.48
		Trp59	Pi-Pi Stacked	4.54
Berberine	-8.4	Asp197	C-H Bond	3.37
		His299	C-H Bond	3.59
		Glu233	C-H Bond	3.34
		His101	Pi-Pi Stacked	4.95
		Trp59	Pi-Pi Stacked	4.90
		Trp58	Pi-Pi T-Shaped	5.28
		His101	Pi-Alkyl	4.95
Alizarin	-8.4	Asp197	Conventional Hydrogen Bond	2.01
		Glu233	Conventional Hydrogen Bond	3.03
		Trp59	Pi-Pi Stacked	5.73
		His299	Pi-Pi Stacked	5.74
		Tyr62	Pi-Pi Stacked	4.94,5.64
		Leu165	Pi-Alkyl	5.46
Jatrorrhizine	-8.3	Asp356	C-H Bond	3.50
		Tyr62	Pi-Pi Stacked	4.97
		Trp59	Pi-Pi Stacked	4.26
		Trp59	Pi-Alkyl	5.82
		His299	Pi-Alkyl	4.43
Rubiadin	-8.2	Gln63	Conventional Hydrogen Bond	2.94
		Trp59	Pi-Sigma	3.91
		Tyr62	Pi-Pi Stacked	4.50,5.69
		Trp59	Pi-Pi Stacked	5.80
		Leu165	Pi-Alkyl	5.38
Myricetin	-8.2	Glu233	Conventional Hydrogen Bond	2.48
		Asp197	Conventional Hydrogen Bond	2.55
		Gln63	Conventional Hydrogen Bond	3.17,2.90
		Tyr62	Pi-Donor Hydrogen Bond	2.44
		Trp59	Pi-Pi Stacked	4.31,5.19
1-Hydroxy-2-methylanthraquinone	-8.1	Gln63	Conventional Hydrogen Bond	3.00
		Trp59	Pi-Pi Stacked	5.16,4.51
Palmatine	-8	Asp197	C-H Bond	3.59
		Glu233	C-H Bond	3.39,3.73,3.77
		Ile235	Pi Sigma	3.86
		Leu165	Alkyl	4.86
		Leu162	Alkyl	5.48
		Lys200	Alkyl	4.69,4.83
		Tyr151	Pi-Alkyl	4.76
		Ile235	Pi-Alkyl	4.11,4.42
		Trp58	Pi-Alkyl	4.81
Ellagic acid	-8	Ser289	Conventional Hydrogen Bond	2.03,2.98
		Gly334	Conventional Hydrogen Bond	2.09
		Arg398	Conventional Hydrogen Bond	3.20
		Thr6	Conventional Hydrogen Bond	2.68
		Thr11	C-H Bond	3.78
		Arg252	Pi-Cation	3.92,3.87
		Asp402	Pi-Anion	4.82,4.95
		Phe335	Pi-Pi T-Shaped	5.11
		Pro4	Pi-Alkyl	4.94
Pterosupin	-7.9	Arg421	Conventional Hydrogen Bond	5.62
		Arg398	Conventional Hydrogen Bond	2.83
		Arg252	Conventional Hydrogen Bond	3.05
		Ser3	Conventional Hydrogen Bond	2.26
		Thr6	Conventional Hydrogen Bond	1.93
		Gln8	Conventional Hydrogen Bond	2.24
		Arg398	Pi-Cation	3.70
		Asp402	Pi-Anion	3.57
		Pro4	Pi-Alkyl	4.50
Pterostilbene	-7.4	Gln63	Conventional Hydrogen Bond	3.07
		Trp59	Pi-Pi Stacked	4.40
		Tyr62	Pi-Pi T-Shaped	4.93
		Leu165	Alkyl	4.66
		Trp59	Pi-Alkyl	5.03
Caffeic acid	-6.7	Glu233	Conventional Hydrogen Bond	2.64
		Asp197	Conventional Hydrogen Bond	2.80
		Gln63	Conventional Hydrogen Bond	3.34
		Tyr62	Pi-Pi Stacked	4.33
Vanillic acid	-5.4	Asp402	Conventional Hydrogen Bond	2.72
		Arg421	Conventional Hydrogen Bond	3.01,5.83
		Pro332	C-H Bond	3.56,3.64
		Arg398	Pi-cation	3.92
		Asp402	Pi-Anion	4.14

2.3. DFT study:

DFT calculations was performed to investigate the electronic and chemical properties of four diverse molecules: Conanine, Friedelin, Sennoside A, and Sennoside B. Through a detailed analysis of key DFT parameters, including the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) energies, the HOMO-LUMO Gap (HLG), ionization potentials (IP), electron affinities (EA), dipole moments (DM), electronegativities, chemical potentials, chemical hardness, and electrophilicities was calculated, study aimed to gain a comprehensive understanding of their reactivity, stability, and overall chemical behavior. The results of this DFT study not only provide valuable insights into the intrinsic properties of these molecules but also lay the groundwork for potential applications in chemical reactions and material design. The calculated chemical reactivity descriptors are represented in Table 2 and the FMO of each molecule is represented in Figure 3.

Conanine exhibited a HOMO energy of -5.676 eV, indicating a relatively low energy required to remove an electron from its HOMO. This suggests that Conanine is more prone to donating electrons, making it potentially suitable for electron-donation reactions. Its LUMO energy of 1.405 eV suggests that it can also accept electrons, albeit with less ease than some other molecules. The HOMO-LUMO Gap (HLG) of 7.08 eV indicates a wide gap, suggesting high chemical stability. The moderate DM of 0.57 Debye suggests a moderate level of polarity. Conanine's IP of 5.68 eV indicates that it resists electron removal, while its EA of -1.41 eV shows an affinity for gaining electrons, albeit not as strongly as some other molecules. Its electronegativity of 2.14 eV suggests a moderate electron-attracting ability. Overall, Conanine possesses a balanced set of properties, making it versatile for various chemical reactions.

Friedelin displayed a HOMO energy of -6.365 eV, indicating a strong tendency to donate electrons, suggesting it can act as a nucleophile in reactions. Conversely, its low LUMO energy of -2.552 eV suggests a readiness to accept electrons, making it a potential electrophile. The narrow HLG of 3.813 eV suggests that Friedelin is relatively stable, and its high DM of 3.343 Debye indicates significant polarity, potentially influencing its solubility and intermolecular interactions. A high IP of 6.365 eV implies resistance to electron removal, while its high EA of 2.552 eV signifies an inclination to gain electrons. Friedelin's electronegativity of 4.458 eV indicates a strong electron-attracting ability. With a negative µ of -4.458 eV, it is positioned as an electron donor. Its low chemical hardness of 1.906 eV suggests reactivity, and the high electrophilicity of 5.213 eV reveals its strong tendency to react with nucleophiles, indicating its potential use in various chemical transformations.

Sennoside A possessed a HOMO energy of -6.358 eV, indicating a strong electron donor characteristic, suggesting it can participate in electron-donation reactions. Its low LUMO energy of -0.434 eV suggests it can readily accept electrons as well. A moderate HLG of 5.924 eV suggests it is moderately stable, while its moderate DM of 3.037 Debye implies some degree of polarity. The high IP of 6.358 eV indicates resistance to electron removal, and the low EA of 0.434 eV suggests reluctance to gain electrons. Sennoside A's electronegativity of 3.396 eV indicates a moderate electron-attracting ability. With a µ of -3.396 eV, it is positioned as an electron donor. A moderate chemical hardness of 2.962 eV suggests moderate reactivity, while the low electrophilicity of 1.946 eV indicates a tendency to act as a nucleophile in reactions.

Sennoside B exhibitd a HOMO energy of -6.605 eV, indicating a strong electron donor characteristic, similar to Sennoside A. Its low LUMO energy of -2.625 eV suggests it can readily accept electrons, making it potentially versatile in electron-donation and -acceptance reactions. A narrow HLG of 3.98 eV suggests it is relatively stable, while its high DM of 6.731 Debye indicates significant polarity, influencing its physicochemical properties. The high IP of 6.605 eV suggests resistance to electron removal, while its high EA of 2.625 eV indicates a strong tendency to gain electrons. Sennoside B's electronegativity of 4.615 eV suggests a robust electron-attracting ability. With a µ of -4.615 eV, it is positioned as an electron donor. Its low chemical hardness of 1.99 eV implies reactivity, and the high electrophilicity of 5.351 eV suggests a strong tendency to react with nucleophiles, making it potentially suitable for various chemical reactions.

Comparing these results revealed distinct properties and reactivity profiles of hits. Friedelin stands out as highly reactive with a strong electrophilic nature, indicating its potential in electron-accepting reactions. Sennoside A and Conanine both have lower ionization potentials, making them more suitable for electron-donation reactions, with Sennoside A having moderate electrophilicity and Sennoside B exhibiting high polarity and reactivity, bridging the gap between electron donor and acceptor characteristics. These DFT insights serve as a valuable foundation for experimental investigations and potential applications in various fields, including pharmaceuticals and materials science.

Figure 3: FMOs for a) b) c) and d).Table 2: Chemical reactivity descriptors calculated using DFT method.

Code	HOMO (eV)	LUMO (eV)	HLG (eV)	DM (Debye)	IP (eV)	EA (eV)	χ (eV)	µ (eV)	η (eV)	ω (eV)
Conanine	-5.676	1.405	7.08	0.57	5.68	-1.41	2.14	-2.14	3.54	0.64
Friedelin	-6.365	-2.552	3.813	3.343	6.365	2.552	4.458	-4.458	1.906	5.213
Sennoside A	-6.358	-0.434	5.924	3.037	6.358	0.434	3.396	-3.396	2.962	1.946
Sennoside B	-6.605	-2.625	3.98	6.731	6.605	2.625	4.615	-4.615	1.99	5.351

4. CONCLUSION:

In conclusion, the comprehensive molecular docking study undertaken in this research has unveiled four promising ligands—Conanine, Friedelin, Sennoside A, and Sennoside B—with exceptional binding affinities exceeding -9kcal/mol when targeted against the specific enzyme α-amylase. Notably, Conanine emerged as the standout performer with the highest negative binding affinity, recorded at -9.5kcal/mol, surpassing the other docked phytochemicals. Sennoside A and Sennoside B, on the other hand, exhibited their efficacy through the formation of multiple hydrogen bonds with the target α-amylase, showcasing their strong binding interactions. Moreover, a subsequent DFT calculation confirmed these ligands' favorable chemical reactivity profiles, characterized by a noteworthy HOMO-LUMO energy gap. The findings from this study hold significant promise for medicinal chemists, as they provide a valuable starting point for the optimization of these ligands, ultimately paving the way for the development of enhanced therapeutic agents. This research not only highlights the potential of these phytochemicals but also underscores the importance of computational methods in drug discovery and the design of novel pharmaceuticals.

5. CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 09.10.2023           Modified on 13.11.2023

Accepted on 07.12.2023          © RJPT All right reserved

Research J. Pharm. and Tech 2024; 17(1):419-426.

DOI: 10.52711/0974-360X.2024.00066