Original Article

A computational Docking and Structure-Activity Relationship analysis of the Phytochemical Isorhamnetin as a potential inhibitor of 2vsm (Glycoprotein of Nipah virus)

 

 

INTRODUCTION

Nipah virus is a Fatal emerging pathogen which belongs to zoonotic diseases are a member of Paramyxoviridae virus family which is a significant global threat regarding public health Chua et al. (2000), Ang et al. (2018). By contamination of this virus fatal encephalitis and respiratory disorders may occurs in human and in some outbreaks, mortality rates already exceeded 70% Ang et al. (2018), Lo and Rota (2008).

The virus attachment is done with the viral attachment Glycoprotein (PDB:2vsm) and it plays a significant role for recognize host cell and viral entry. This make it an attractive target for antiviral drug development Newman and Cragg (2020).

Natural herbal compounds, particularly secondary metabolites under the domain of flavonoids gets its attention due to the antiviral and other safety properties Clayton (2017).

The Isorhamnetin is a secondary metabolites of Acacia catechu which is a well known plant used as medicinal plants in Indian traditional therapeutic system. This phytochemical of  Acacia catechu is a methylated flavonol and has the antiviral, antioxidant and anti-inflammatory properties Calderón-Montaño et al. (2011)

The aim of this study is to reveal potential that inhibitors properties of Isorhamnetin against the Glycoprotein. The study demonstrated binding interactions through molecular docking and SAR analysis.

 

Materials and Methods

The crystal 3D structure of the Glycoprotein of Nipah virus (PDB ID: 2VSM) was searched out from the RCSB Protein Data Bank Database.

 

2vsm the PDB Number of glycoprotein of Nipah Virus. The structure contains Chain A, which is virus content and Chain B which is human control surface receptor ephrinB2 Xu et al. (2008). For that reason the download PDB file was taken to Discovery Studio where Chain B was eliminated. After that all the heteroatom and water was removed by the protein structure and Kollman charges were added and saved the file as PFBQT format.

 

Ligand Preparation

 

The 3D sdf file of Isorhamnetin was obtained from PubChem. Then it was taken to OpenBable to find out the PDB structure. The ligand, Isorhamnetin was taken to Avogadro2 software for was energy-minimized with MMFF94 force field and hydrogen atoms were added. Then Gasteiger charges were assigned and converted it into PDBQT format.

 

Molecular Docking

Both PDBQT file was taken to AutoDock 4.2 software. Lamarckian Genetic Algorithm was applied. The grid box was centered around the active binding pocket of 2VSM. AutoGrid and AutoDock was applied for molecular docking and the docking log (.dlg) file was analyzed to extract binding energies and interaction conformations.

 

Structure–Activity Relationship (SAR) Analysis

SAR analysis was performed to evaluate the role of functional groups in ligand binding. Structural features such as hydroxyl groups, methoxy substitution, and aromatic rings were correlated with binding affinity.

 

Results and Discussion (Docking and Structure–Activity Relationship)

The analysis of Molecular Docking of 2bsm with Isorhamnetin 2VSM showed a binding energy of −6.32 kcal/mol, that indicates a strong interaction and good binding stability. The Isorhamnetin as a ligand was occupy the active binding site of the glycoprotein efficiently which revealed it’s potentiality as an antiviral inhibitor. The results of docking ( .dlg file) showed a strong binding energy, which was suggested that the Isorhamnetin ligand was generated a stable complex within the binding active site of the protein. The binding model demonstrated that ligand is well accommodated in the 2vsm (receptor) cavity, adopting an position that maximizes intermolecular interactions.

 

Interaction Analysis of Molecular Docking

Detailed analysis of the docked complex showed that ligand Isorhamnetin  poses multiple hydrogen bonds with key polar residues like Ser and Asn, which are vital for anchoring the ligand Isorhamnetin within the binding pocket. These transactions arise primarily from the hydroxyl (–OH) groups which are present on the flavonoid scaffold, which act as both hydrogen bond donors and acceptors. Such interactions significantly enhance binding specificity and stability.

In addition to polar transaction, the ligand Isorhamnetin also engages in hydrophobic relations with non-polar amino acid residues including Leu and Val, inside the binding cavity. These transactions contribute to the stabilization of the ligand Isorhamnetin  through van der Waals forces and hydrophobic packing. The presence of a methoxy (–OCH₃) group in isorhamnetin increases its lipophilicity, thereby strengthening its interaction with hydrophobic regions of the protein.

A vital feature shown in the docking study is the presence of π–π stacking interactions between the aromatic rings of ligand Isorhamnetin and aromatic residues such as phenylalanine and tyrosine. The planar flavonoid backbone enables effective overlap of π-electron clouds with these residues at an optimal distance (~3.5 – 4.5 Å), causes to enhanced electronic stabilization. These π–π transaction play a crucial role in reinforcing the ligand–protein complex and improving binding affinity.

 

SAR (Structure–Activity Relationship) Interpretation

Key Interacting Residues

Hydrogen Bonds: Asn557, Ser561, Lys560

Hydrophobic Interactions: Leu552, Val555

Van der Waals interactions: Tyr581 and surrounding residues

The inhibitory activity of ligand Isorhamnetin can be directly correlated with its structural features:

Methoxy Substitution (–OCH₃)

The methoxy group helps to increased lipophilicity, facilitating better interaction with hydrophobic amino acids such as Leu and Val. This modification also helps in improving membrane permeability, an important pharmacokinetic property.

Hydroxyl Groups (–OH)

The presence of multiple hydroxyl groups secure the formation of good hydrogen bonds with active site residues, thereby increasing binding affinity and specificity.

Flavonoid Aromatic Backbone

The rigid and planar structure of the flavonoid core ensures optimal alignment within the binding pocket. This structural rigidity minimizes conformational entropy loss upon binding and promotes π–π stacking interactions with aromatic residues, further stabilizing the complex.

Synergistic Effect of Functional Groups

The combined presence of hydrogen bonding groups, hydrophobic substituents, and aromatic rings creates a multi-interaction binding mechanism, which significantly enhances the overall inhibitory potential of the molecule.

Integrated Insight

The docking results and SAR analysis collectively demonstrate that ligand Isorhamnetin exhibits a multi-modal interaction profile involving hydrogen bonding, hydrophobic interactions, and π–π stacking. This combination of interactions leads to a highly stable ligand–protein complex, which is essential for effective inhibition of the Nipah virus glycoprotein, 2vsm.

 

The study highlights that structural optimization of flavonoid derivatives, particularly through modification of hydroxyl and methoxy groups, could further enhance antiviral activity. Therefore, isorhamnetin serves as a promising lead compound for the development of novel therapeutics targeting Nipah virus infection.

 

Conclusion

This study shows that ligand Isorhamnetin exhibits strong binding affinity and stable transactions with the Nipah virus glycoprotein (2VSM). The docking results, supported by SAR analysis, indicate that functional groups such as hydroxyl and methoxy moieties play a vital role in enhancing inhibitory activity. The interaction with key residues such as Asn557, Ser561, and Lys560 highlights its potential as a promising antiviral candidate.

Further studied Xu et al. (2008), including molecular dynamics simulations and experimental validation, are required to confirm its therapeutic efficacy.

  

ACKNOWLEDGMENTS

None.

 

REFERENCES

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