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ISSN 2278-2540 | DOI: 10.51583/IJLTEMAS | Volume XIV, Issue XI, November 2025  
Molecular Docking Analysis of Phytocompounds from Hyptis  
Verticillata as Potential Inhibitors of Human Cyclooxygenase-2  
(COX-2)  
Dearsly, Emmanuel Markus1: Dada, Emmanuel Damilo1: Eze, Kingsley Chijioke2: Akwagiobe,  
Emmanuel Ushigianle2: Oshatuyi Olukayode2: Emmanuel Ikegima1: Adaji Princess Ojoma3  
1Department of Biochemistry, College of Natural and Applied Sciences, Salem University, Kogi State,  
Nigeria  
2Department of Biochemistry, Faculty of Basic Medical Sciences, University of Calabar Nigeria  
3Department of Biochemistry, Faculty of Basic Medical and Health Sciences, Thomas Adewumi  
University, Oko-Irese, Kwara State, Nigeria.  
DOI: https://doi.org/10.51583/IJLTEMAS.2025.1411000012  
Received: 16 November 2025; Accepted: 24 November 2025; Published: 02 December 2025  
ABSTRACT  
Cyclooxygenase-2 (COX-2) is a key inducible enzyme in the inflammatory pathway, catalyzing the conversion  
of arachidonic acid into prostaglandins that mediate pain, fever, and inflammation. Selective COX-2 inhibitors  
such as celecoxib and rofecoxib have demonstrated strong therapeutic effects but are associated with adverse  
cardiovascular and gastrointestinal complications, underscoring the need for safer alternatives. Medicinal plants  
represent a valuable source of novel bioactive compounds with promising anti-inflammatory properties. Hyptis  
verticillata, a member of the Lamiaceae family, has been widely used in ethnomedicine for treating fever, colds,  
and inflammatory conditions, and is known to contain diverse phytochemicals including terpenoids, flavonoids,  
sterols, and essential oils. This study aimed to evaluate the molecular docking interactions of phytocompounds  
from H. verticillata with human COX-2 (PDB ID: 6COX) as potential natural anti-inflammatory agents. Seven  
phytochemicals reported in previous phytochemical profiling of the plant were docked against the COX-2 active  
site using AutoDock Vina implemented in PyRx, and their interactions compared with reference inhibitors  
celecoxib and rofecoxib. Binding affinities ranged from −3.7 to −8.2 kcal/mol. Squalene demonstrated the  
strongest affinity (−8.2 kcal/mol), comparable to rofecoxib (−8.2 kcal/mol), while aliphatic hydrocarbons such  
as 1-octadecyne (−6.9 kcal/mol) and 1-fluorodecane (−6.1 kcal/mol) showed moderate activity. Celecoxib,  
unexpectedly scoring −3.7 kcal/mol, highlighted potential docking protocol limitations that warrant revalidation.  
Interaction analysis revealed that hydrophobic contacts dominated ligand binding, consistent with the structural  
hydrophobicity of the COX-2 catalytic tunnel. Although squalene showed high docking affinity, ADMET  
predictions indicated poor solubility and oral bioavailability, limiting its drug-likeness. In contrast, smaller  
hydrocarbons displayed more favorable pharmacokinetic profiles but weaker binding energies. These findings  
suggest that H. verticillata harbors compounds with structural potential for COX-2 inhibition, though  
optimization and experimental validation are required. The study provides a computational foundation for  
developing safer plant-derived anti-inflammatory agents.  
Keywords: Hyptis verticillata, cyclooxygenase-2, molecular docking, phytochemicals, anti-inflammatory,  
ADMET.  
INTRODUCTION  
Inflammation is a central biological process that plays both protective and pathological roles in the human body.  
While acute inflammation is essential for host defense and tissue repair, chronic inflammation contributes to the  
pathogenesis of various diseases, including cancer, cardiovascular diseases, diabetes, rheumatoid arthritis, and  
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neurodegenerative disorders (Medzhitov, 2008). One of the key enzymes in the inflammatory cascade is  
cyclooxygenase (COX), which exists in two isoforms: COX-1 and COX-2.  
COX-1 is constitutively expressed and maintains physiological functions such as gastric mucosal protection and  
platelet aggregation, whereas COX-2 is inducible and upregulated in response to pro-inflammatory stimuli like  
cytokines and endotoxins (Chandrasekharan et al., 2002). COX-2 catalyzes the conversion of arachidonic acid  
to prostaglandin H2, a precursor for pro-inflammatory prostaglandins and thromboxanes (Rouzer & Marnett,  
2009). The structural substitution of isoleucine-523 in COX-1 with valine-523 in COX-2 creates a secondary  
pocket, enabling selective inhibition of COX-2 by coxibs such as celecoxib and rofecoxib (Kurumbail et al.,  
1996).  
Despite the therapeutic potential of COX-2 inhibition, conventional non-steroidal anti-inflammatory drugs  
(NSAIDs) and coxibs are associated with adverse effects including gastrointestinal toxicity, renal impairment,  
and cardiovascular complications (Hinz & Brune, 2002). This has driven the search for natural COX-2 inhibitors  
with safer pharmacological profiles. Medicinal plants are a promising source of novel bioactive compounds, and  
ethnopharmacological knowledge has guided the discovery of many therapeutic agents.  
Hyptis verticillata Jacq., commonly known as John Charles, is a perennial herb belonging to the family  
Lamiaceae. The plant is widely distributed in tropical regions, including Africa and the Caribbean, and has been  
traditionally used in folk medicine for managing fever, colds, gastrointestinal disorders, and inflammatory  
conditions (Adesina, 1982; Lans, 2006). Phytochemical studies have revealed that H. verticillata contains  
essential oils, flavonoids, terpenoids, fatty acid esters, and alkaloids with diverse biological activities (Ajiboye  
et al., 2018). GC-MS profiling of its leaf extracts from Nigeria confirmed the presence of hydrocarbons, fatty  
acid esters, and sterols, some of which have reported anti-inflammatory and antimicrobial properties (Ajiboye  
et al., 2018).  
Given its ethnomedicinal relevance and phytochemical diversity, H. verticillata represents a potential source of  
novel COX-2 inhibitors. However, the molecular interactions between its bioactive compounds and the COX-2  
active site remain unexplored. Computational approaches such as molecular docking provide valuable insights  
into ligand–receptor interactions, binding affinity, and structure-activity relationships, thereby accelerating drug  
discovery (Kitchen et al., 2004).  
Statement of the Problem  
Conventional NSAIDs and selective COX-2 inhibitors are effective anti-inflammatory agents but pose risks of  
gastrointestinal and cardiovascular toxicity. There is a need for safer, plant-derived alternatives that can inhibit  
COX-2 effectively while minimizing adverse effects. Hyptis verticillata is traditionally used in treating  
inflammation-related conditions, but its molecular potential as a COX-2 inhibitor has not been systematically  
evaluated.  
Aim of the study  
This study aims to evaluate the molecular docking interactions of phytocompounds derived from Hyptis  
verticillata with the human cyclooxygenase-2 (COX-2) enzyme (PDB ID: 6COX). The goal is to determine their  
potential as natural anti-inflammatory agents by analyzing binding affinities and molecular interactions. Selected  
phytochemicals will be compared against standard reference inhibitors such as celecoxib and rofecoxib. This  
research seeks to highlight promising compounds that may serve as leads in drug discovery for COX-2 inhibition.  
Ultimately, the study provides a computational foundation for future pharmacological validation.  
MATERIALS AND METHODS  
Study Design  
This study employed an in-silico design involving molecular docking simulations of phytochemicals from H.  
verticillata against COX-2. Comparative docking with reference inhibitors was used for validation.  
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Insilico analysis  
The databases used includes:  
1.  
2.  
3.  
4.  
5.  
6.  
PubMed Database (https://pubmed.ncbi.nlm.nih.gov/)  
PubChem (https://pubchem.ncbi.nlm.nih.gov/)  
RCSB-Protein Data Bank (https://www.rcsb.org/)  
Chemspider (http://www.chemspider.com/)  
Swissadme (http://www.swissadme.ch/)  
ADMET lab 2.0 (https://admetmesh.scbdd.com/)  
Softwares used includes:  
1.  
2.  
3.  
OpenBabel in build in PyRx 0.8  
Discovery Studio 2024  
AutoDock Vina in built in PyRx 0.8  
Protein Preparation  
The 3D crystal structure of human cyclooxygenase-2 bound to the selective inhibitor SC-558 was retrieved  
from the RCSB Protein Data Bank (PDB ID: 6COX) at 2.8 Å resolution (Kurumbail et al., 1996). Protein  
preparation involved:  
Removal of co-crystallized ligand (SC-558) and water molecules.  
Retention of the heme cofactor essential for enzyme activity.  
Addition of polar hydrogens and assignment of Kollman charges using AutoDock Tools 1.5.6.  
Energy minimization and conversion to PDBQT format.  
Table 1 Selected receptors in PCOS  
TARGET PROTEIN  
COX-2  
ID NUMBER  
6COX  
Ligand Preparation  
7 bioactive phytochemicals in structured Data Format (SDF) from H. verticillata, were retrieved from the  
PubChem database, PubMed Database and the Ligand molecules were further converted to the dockable PDBQT  
format using AutoDock Tools.  
Referenced drugs  
Celecoxib (PDB ligand ID: CLX) – a selective COX-2 inhibitor, clinically used as an anti-inflammatory and  
analgesic (arthritis, pain, etc.).  
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Rofecoxib (Vioxx) – another selective COX-2 inhibitor, widely studied though withdrawn from the market due  
to cardiovascular risk.  
Table 2 List of phytocompounds and referenced drugs  
Ligands  
3a.4,5,6,7,7a-hexahydro-4,7-methanoindene  
4,7- methanon-1H-indene  
R-R,R-E- trans-Phytol  
Squalene  
9,12,15-octadecatrien-1-ol  
1-octadecyne  
1-fluorodecane  
Rofecoxib  
Colecoxib  
Docking Procedure  
Docking was performed using AutoDock Vina integrated in PyRx 0.8.  
The grid box was centered at the SC-558 binding site with dimensions of 25 Å × 25 Å × 25 Å.  
Exhaustiveness was set at 8 for accurate conformational sampling.  
Each ligand was docked to generate up to 10 binding poses ranked by binding affinity (kcal/mol).  
Interaction Analysis  
Discovery Studio Visualizer 2024 was used to analyze protein–ligand interactions, focusing on:  
Hydrogen bonding  
Hydrophobic contacts  
π–π interactions  
ADMET and Drug-Likeness Analysis  
SwissADME (Daina et al., 2017) and ADMETlab 2.0 were used to predict pharmacokinetic properties of the  
top docked phytocompounds, assessing:  
Lipinski’s rule of five compliance  
Absorption and distribution  
Toxicity predictions (hepatotoxicity, mutagenicity)  
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RESULTS AND DISCUSSION  
Molecular docking results  
The results of molecular docking against the selected receptor are shown below as represented by the docking  
scores. The docking scores of the compounds range from -3.7 to -8.2.  
TABLE 3 Docking score of phytochemicals from Hyptis Verticillata with receptor  
Ligands  
Binding Affinity  
1CX2  
-4.3  
-4.3  
-5.3  
-8.2  
-5.2  
-6.9  
-6.1  
-8.2  
-3.7  
3a.4,5,6,7,7a-hexahydro-4,7-methanoindene  
4,7- methanon-1H-indene  
R-R,R-E- trans-Phytol  
Squalene  
9,12,15-octadecatrien-1-ol  
1-octadecyne  
1-fluorodecane  
Rofecoxib  
Colecoxib  
Drug-likeness screening result  
TABLE 4 Drug-likeness screening result of phytocompounds from Hyptis Verticillata  
Compounds  
Lipinski Ghose Veber Egan Muegge Remark  
3a.4,5,6,7,7a-hexahydro-4,7-  
methanoindene  
Yes  
No  
Yes  
Yes No  
No  
4,7- methanon-1H-indene  
R-R,R-E- trans-Phytol  
Squalene  
Yes  
Yes  
Yes  
Yes  
Yes  
Yes  
No  
No  
No  
Yes  
No  
Yes  
Yes  
Yes  
Yes  
Yes  
No  
Yes No  
No  
No  
No  
No  
No  
No  
No  
9,12,15-octadecatrien-1-ol  
1-octadecyne  
Yes No  
No No  
Yes No  
Passed  
No  
1-fluorodecane  
Yes  
Passed  
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Evaluation of high binding affinity in comparison with selected REF drug  
TABLE 5 Docking results of compound with high binding affinity with rofecoxib  
Ligands  
Squalene  
Binding Affinity  
-8.2  
-8.2  
Rofecoxib (Referenced drug)  
Figure 1. COX2 - Squalene interaction: (2D) & (3D) surface view  
Schematic representation of main interaction of squalene interaction with COX2, purple color represents  
hydrophobic bond.  
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Figure 2. COX2 - Rofecoxib interaction: (2D) & (3D) surface view  
Schematic representation of main interaction of rofecoxib squalene interaction with COX2, purple represents  
hydrophobic bond.  
ADMET RESULT  
Figure 3. ADMET result of Squalene  
Figure 4. ADMET result of Rofecoxib  
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RESULTS AND DISCUSSION  
Docking Outputs  
Molecular docking of seven Hyptis verticillata phytocompounds against the COX-2 binding site produced  
binding affinities ranging from −3.7 to −8.2 kcal/mol. The top-scoring ligand was squalene (−8.2 kcal/mol),  
which tied with the reference inhibitor rofecoxib (−8.2 kcal/mol). Intermediate scores were observed for 1-  
octadecyne (−6.9 kcal/mol) and 1-fluorodecane (−6.1 kcal/mol), whereas R-R,R-E-trans-phytol (−5.3 kcal/mol),  
9,12,15-octadecatrien-1-ol (−5.2 kcal/mol), and the bicyclic indene derivatives (−4.3 kcal/mol) were lower. The  
draft table lists “Colecoxib” at −3.7 kcal/mol, which we interpret as celecoxib; this unexpectedly weak score is  
evaluated below in the context of known structural pharmacology (Kurumbail et al., 1996; Wang et al., 2010).  
The docking was performed using PDB 6COX, a murine COX-2 crystal structure co-crystallized with the  
selective inhibitor SC-558 at 2.8 Å resolution. Although 6COX is a widely used structural surrogate for human  
COX-2, the species difference should be kept in mind when interpreting absolute scores and residue-level  
contacts (Kurumbail et al., 1996).  
Rank Order and Comparison to Reference Drugs  
Squalene matched rofecoxib (−8.2 vs −8.2 kcal/mol), placing both at the top of the ranking. This parity suggests  
that squalene can occupy the predominantly hydrophobic COX-2 cyclooxygenase channel with favorable van  
der Waals complementarity. However, docking energy alone is not a surrogate for drug potential because  
squalene violates several drug-likeness filters and lacks polar functionalities needed for specific interactions  
(Zarghi & Arfaei, 2011). The mid-tier ligands (1-octadecyne and 1-fluorodecane) performed better than  
oxygenated chains (phytol; octadecatrienol) and much better than the rigid bicyclic indenes, consistent with the  
notion that shape complementarity and lipophilicity drive affinity in the long, hydrophobic COX-2 channel. This  
trend aligns with the known structural pharmacology of COX-2, where a Val-523 substitution creates a side  
pocket that selectively accommodates bulkier, lipophilic motifs present in coxibs (Kurumbail et al., 1996).  
The celecoxib score was unexpectedly weak relative to rofecoxib. Possible explanations include misassignment  
of the sulfonamide protonation state, grid misplacement, or the murine-human difference in binding pockets.  
Literature shows celecoxib consistently binds strongly in human COX-2 structures such as PDB 3LN1 (Wang et  
al., 2010).  
Binding-Mode Interpretation  
Interaction depictions for squalene and rofecoxib show predominantly hydrophobic contacts, consistent with the  
non-polar interior of the COX-2 cyclooxygenase channel. Rofecoxib’s sulfonyl-aryl motif engages the secondary  
pocket enabled by Val-523, a known determinant of selectivity (Kurumbail et al., 1996). Squalene, in contrast,  
relies on sheer hydrophobic surface coverage. The indenes scored poorly due to limited occupancy of the  
extended hydrophobic tunnel. Long aliphatic chains (e.g., octadecyne) align better but lack direct anchor points  
such as hydrogen bonds with Arg-120 and Tyr-355, residues often engaged by NSAIDs (Smith et al., 2000).  
Drug-Likeness and ADMET Analysis  
Drug-likeness filtering showed that squalene passed Lipinski but failed multiple other filters, while smaller  
aliphatic molecules passed more rules. SwissADME predictions suggested squalene’s poor solubility and GI  
absorption, whereas rofecoxib had more balanced oral drug properties but known cardiovascular risk (Daina et  
al., 2017; Mukherjee et al., 2001). This highlights that docking affinity must be complemented by  
pharmacokinetic evaluation.  
Practical Implications  
Squalene demonstrated high affinity but poor drug-likeness, making it unsuitable as a direct lead but  
useful as a chemotype inspiration.  
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Aliphatic hydrocarbons showed moderate potential and could be optimized through addition of polar  
anchor groups.  
Celecoxib and rofecoxib validate the docking system, though parameter refinement is necessary for  
accurate benchmarking (Zarghi & Arfaei, 2011).  
CONCLUSION  
This study explored the molecular docking interactions of phytocompounds from Hyptis verticillata with  
cyclooxygenase-2 (COX-2) to assess their potential as natural anti-inflammatory agents. The docking analysis  
revealed that squalene exhibited the strongest binding affinity (−8.2 kcal/mol), comparable to the reference  
inhibitor rofecoxib, suggesting that hydrophobic terpenoids from H. verticillata can effectively occupy the COX-  
2 active site. Other compounds such as 1-octadecyne (−6.9 kcal/mol) and 1-fluorodecane (−6.1 kcal/mol)  
demonstrated moderate binding energies, while oxygenated derivatives and indenes showed weaker interactions.  
Interaction profiling confirmed that hydrophobic contacts were the dominant stabilizing forces, consistent with  
the lipophilic architecture of the COX-2 catalytic tunnel. However, drug-likeness and ADMET analysis indicated  
that squalene, despite its strong binding affinity, may suffer from poor solubility and oral bioavailability, limiting  
its direct drug development potential. In contrast, smaller aliphatic compounds displayed more favorable  
pharmacokinetic properties but lower binding affinities, suggesting they could serve as starting points for  
optimization.  
The study underscores the therapeutic promise of H. verticillata phytochemicals as potential COX-2 inhibitors  
while also highlighting the importance of balancing binding affinity with pharmacokinetic suitability. Overall,  
these findings provide a computational foundation for further structure-based drug design, molecular dynamics  
validation, and experimental studies to advance the development of safer plant-derived anti-inflammatory  
agents.  
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