INTERNATIONAL JOURNAL OF RESEARCH AND INNOVATION IN APPLIED SCIENCE (IJRIAS)  
ISSN No. 2454-6194 | DOI: 10.51584/IJRIAS |Volume X Issue XI November 2025  
In Silico Evaluation of Hyptis Verticillata-Derived Phytochemicals  
Targeting Estrogen Receptor Alpha (Erα) and Progesterone Receptor  
in Hormone-Dependent Breast Cancer  
Oshatuyi Olukayode2: *Dearsly, Emmanuel Markus1: Emmanuel Ofutet3: Ogidigo, Jane Chinwe2:  
Dada, Emmanuel Damilo1: Okoo, Blessing Ahiowawanyohe4: Peter Janet1: Emmanuel Ikegima1  
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 Physiology, Faculty of Medicine and Pharmaceutical sciences, Kampala international  
university, Dar es salaam, Tanzania  
4Department of Biological Sciences, Faculty of Science, Benue State University  
*Corresponding Author  
DOI: https://dx.doi.org/10.51584/IJRIAS.2025.101100020  
Received: 18 November 2025; Accepted: 27 November 2025; Published: 04 December 2025  
ABSTRACT  
Hormone-dependent breast cancers, primarily driven by estrogen receptor alpha (ERα) and progesterone receptor  
(PR) signaling, account for most breast malignancies and remain a major therapeutic challenge due to frequent  
resistance to endocrine therapy. The search for novel, plant-derived ligands with dual modulatory activity on  
ERα and PR is therefore critical. This study employed an in silico approach to evaluate selected phytochemicals  
from Hyptis verticillata—a medicinal plant known for its diverse bioactive constituents—against ERα (Y537S  
mutant; PDB ID: 6CHZ) and PR (PDB ID: 4A2J). Seven phytocompounds were retrieved from the PubChem  
database and subjected to drug-likeness analysis using SwissADME, molecular docking with AutoDock Vina,  
and pharmacokinetic/toxicity prediction via ADMETlab 2.0. Among the screened compounds, squalene (−6.9  
kcal/mol) and 4,7-methanon-1H-indene (−6.4 kcal/mol) demonstrated the highest binding affinities toward ERα  
and PR, respectively. Both ligands showed favorable hydrophobic interactions within the receptor ligand-binding  
domains, suggesting potential receptor antagonism or modulation. Drug-likeness and ADMET profiling revealed  
that 3a,4,5,6,7,7a-hexahydro-4,7-methanoindene and 4,7-methanon-1H-indene possess acceptable  
physicochemical and pharmacokinetic properties, indicating promising oral bioavailability and low toxicity  
risks. The findings highlight H. verticillata phytochemicals as potential scaffolds for developing multitargeted  
agents capable of counteracting endocrine resistance in hormone receptor–positive breast cancers. Further  
validation through molecular dynamics simulations and in vitro receptor-binding assays is recommended to  
confirm these computational predictions and explore their mechanistic potential.  
Keywords: Hyptis verticillata, estrogen receptor alpha (ERα), progesterone receptor (PR), molecular docking,  
breast cancer, phytochemicals, endocrine resistance, ADMET profiling.  
INTRODUCTION  
Hormone-dependent (estrogen and/or progesterone receptor–positive) breast cancers account for the majority of  
breast tumors and are driven largely by estrogen receptor-alpha (ERα) signaling, which promotes proliferation  
and survival through genomic and non-genomic pathways (A Basic Review on Estrogen Receptor Signaling  
Pathways in Breast Cancer, 2023; Targeting mutated estrogen receptor alpha: Rediscovering old and new  
opportunities, 2020). Crosstalk between ERα and other steroid receptors—notably the progesterone receptor  
(PR)—adds further regulatory complexity, influencing chromatin binding patterns, transcriptional programs, and  
therapeutic response (Estrogen Receptor Signaling in Breast Cancer, 2023; Genome-wide crosstalk between  
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steroid receptors in breast and prostate cancers, 2021). While endocrine therapies (e.g., SERMs, AIs, SERDs)  
have transformed outcomes, resistance remains common in advanced disease, with ligand-binding domain ESR1  
mutations (e.g., Y537S, D538G) conferring ligand-independent activity and diminishing endocrine sensitivity  
(Mechanisms of endocrine resistance in hormone receptor-positive breast cancer, 2024; ESR1 Y537S and  
D538G Mutations Drive Resistance to CDK4/6 Inhibitors, 2025). Emerging data also highlight PR-mediated  
tumor-immune evasion (e.g., MHC-I downregulation), suggesting PR as both a biological driver and a  
therapeutic vulnerability in HR+ disease (Progesterone receptor–dependent downregulation of MHC class I,  
2025).  
Natural products remain a prolific source of anticancer leads, and in silico pipelines—combining molecular  
docking, molecular dynamics (MD), and ADMET prediction—accelerate early discovery while reducing cost  
and attrition (In silico design of novel bioactive molecules to treat breast cancer, 2023). Hyptis verticillata  
(Lamiaceae) is a medicinal plant whose extracts and essential oils contain diverse sesquiterpenoids and phenolic  
constituents (e.g., squamulosone; cadina-4,10(15)-dien-3-one) with reported bioactivities (Biological activity  
and chemical composition of the essential oil from Hyptis verticillata, 2005; Anti-hyperglycemic potential of  
Hyptis verticillata Jacq., 2018). Despite this chemical richness, systematic evaluation of H. verticillata  
phytochemicals against ERα and PR—especially in the context of clinically relevant ERα mutants—remains  
underexplored. Given the centrality of ERα/PR signaling and the need for novel, resistance-competent  
modulators, in silico screening of H. verticillata–derived compounds is timely and potentially impactful  
(Treating ER-positive breast cancer: a review of current FDA-approved therapies and novel approaches, 2025;  
Beyond endocrine resistance: ESR1 activating mutations, 2024).  
Problem Statement  
Endocrine resistance driven by ESR1 mutations and signaling crosstalk limits the durability of current therapies  
in hormone-dependent breast cancer (Mechanisms of endocrine resistance in hormone receptor-positive breast  
cancer, 2024; Estrogen/HER2 receptor crosstalk in breast cancer, 2023). Although natural products offer  
chemically diverse scaffolds, there is a specific evidence gap: the ERα/PR-targeting potential of characterized  
H. verticillata phytochemicals has not been systematically mapped using modern in silico workflows that  
consider wild-type and mutant ERα, PR interactions, and early drug-likeness/toxicity filters. Additionally, PR’s  
emerging role in immune evasion underscores the need to identify ligands that could modulate PR signaling in  
therapeutically favorable ways (Progesterone receptor–dependent downregulation of MHC class I, 2025).  
Addressing these gaps could yield lead compounds with improved prospects against resistance mechanisms and  
provide hypotheses for downstream in vitro validation.  
Aim of the study  
To perform a comprehensive in silico evaluation of Hyptis verticillata–derived phytochemicals against estrogen  
receptor-alpha (ERα) and progesterone receptor (PR) in hormone-dependent breast cancer.  
MATERIALS AND METHODS  
Materials  
The databases used include:  
1. PubMed Database (https://pubmed.ncbi.nlm.nih.gov/)  
2. PubChem (https://pubchem.ncbi.nlm.nih.gov/)  
3. RCSB-Protein Data Bank (https://www.rcsb.org/)  
4. Chemspider (http://www.chemspider.com/)  
5. Swissadme (http://www.swissadme.ch/)  
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6. ADMET lab 2.0 (https://admetmesh.scbdd.com/)  
Softwares used include:  
1. OpenBabel in build in PyRx 0.8  
2. Discovery Studio 2022  
3. AutoDock Vina in built in PyRx 0.8  
Phytochemical Library Preparation  
Canonical 2D structures (SDF) were downloaded from PubChem for each compound and converted to 3D with  
Open Babel, generating low-energy conformers by weighted rotor search and minimizing with the MMFF94  
force field until the energy gradient fell below 0.05 kcal mol⁻¹ Å⁻¹ (Halgren, 1996; O’Boyle et al., 2011; Kim et  
al., 2021). All structures were neutralized as appropriate for pH 7.4, explicit hydrogens were added, and  
tautomers were standardized. Final ligands were exported to PDBQT using ADT (Morris et al., 2009).  
Table 1 List of phytocompounds derived from hyptis verticilata  
Ligands  
1. 3a.4,5,6,7,7a-hexahydro-4,7-methanoindene  
2. 4,7- methanon-1H-indene  
3. R-R,R-E- trans-Phytol  
4. Squalene  
5. 9,12,15-octadecatrien-1-ol  
6. 1-octadecyne  
7. 1-fluorodecane  
Drug likeness screening  
The compounds were subjected to various drug-likeness filtering analysis. The drug-likeness analysis which  
includes Lipinski, Veber, Ghose, Egan and Muegge were performed on the SwissADME webserver. Drug-  
likeness properties of the compound were screen using the Lipinski’s rule (molecular mass (MM) less than 500  
Da, no more than 5 hydrogen bond donors (HBD), no more than 10 hydrogen bond acceptors (HBA), and  
partition coefficient (log p). (Dearsly et al., 2025)  
Target Protein Selection and Preparation  
Targets were chosen to represent clinically relevant hormone-dependent breast-cancer mechanisms: estrogen  
receptor alpha (ERα) and progesterone receptor (PR).  
ERα Y537S mutant: constitutively active mutation common in endocrine-resistant disease; we used  
structures such as PDB 6CHZ (Y537S bound to a covalent antagonist) (Larsen et al., 2018; Cancer  
Discovery primary paper) to capture mutant LBD geometry (Toy et al., 2017)  
Progesterone receptor (PR) LBD: asoprisnil-bound agonist-state LBD (PDB 4A2J) as a high-resolution  
reference for docking in the canonical PR pocket (Lusher et al., 2012).  
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Table 2 Selected receptors in PCOS  
TARGET PROTEIN  
1. ERα Y537S  
ID NUMBER  
6CHZ  
2. Progesterone receptor (PR)  
4A2J  
Figure 1: 3D structure of ERα Y537S Receptor  
Figure 2: 3D structure of Progesterone receptor (PR)  
Protein preparation followed a standard AutoDock/ADT workflow (Morris et al., 2009): each PDB file was  
inspected; non-essential water molecules, buffer ions, and hetero-ligands (except the co-crystallized reference  
ligand used to define the binding site) were removed; missing side-chain atoms were rebuilt where necessary;  
Kollman/United-Atom charges were applied to the receptor; polar hydrogens were added; and a single receptor  
chain per biological LBD dimer was retained for docking. Prepared receptors were saved as PDBQT (grid maps  
generated on-the-fly by Vina). When needed, original co-crystal ligands were preserved temporarily to define  
the grid box center. (Berman et al., 2000; Morris et al., 2009).  
Molecular Docking  
Docking was performed with AutoDock Vina (Trott & Olson, 2010) using the Vina 1.2 branch to align with  
current best practices (Eberhardt et al., 2021). For each target, the grid box was centered on the coordinates of  
the co-crystallized ligand (3ERT: 4-OHT; 4Q50: 4-OHT; 6CHZ: antagonist bound; 4A2J: asoprisnil) and  
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expanded to encompass the orthosteric pocket plus a 4–6 Å margin to allow side-chain accommodation. Grid  
sizes were typically ~22–26 Å per axis, adjusted to fully cover the pocket while avoiding spurious surface  
binding. The exhaustiveness parameter was set to 16–24 for screening and increased to 32 for final rescoring of  
top candidates; num_modes was 20 with energy_range 3–5 kcal mol⁻¹. All other parameters were left at  
defaults. For each ligand, the best-scoring pose (lowest ΔGbind in kcal mol⁻¹) was retained. (Trott & Olson,  
2010; Eberhardt et al., 2021).  
Docking Protocol Validation (redocking control)  
To ensure pose reliability, we re-docked the native ligands into their respective prepared receptors and  
computed heavy-atom RMSD between the re-docked and crystallographic poses. An RMSD ≤ 2.0 Å was  
considered acceptable, consistent with widely used docking benchmarks (Wang et al., 2003; Warren et al., 2006).  
RESULTS AND DISCUSSION  
Drug-likeness screening result  
Table 3 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  
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 -4.5 to -6.9.  
Table 4 Docking score of phytochemicals from Hyptis Verticillata with receptor  
Ligands  
Binding Affinity  
6CHZ  
4A2J  
-6.4  
-6.4  
-6.6  
-5.4  
1. 3a.4,5,6,7,7a-hexahydro-4,7-methanoindene -6.3  
2. 4,7- methanon-1H-indene  
-6.4  
-6.0  
-6.9  
3. R-R,R-E- trans-Phytol  
4. Squalene  
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5. 9,12,15-octadecatrien-1-ol  
6. 1-octadecyne  
-6.0  
-5.8  
-5.1  
-5.2  
7. 1-fluorodecane  
-4.5  
-4.9  
2D structure of compounds with high binding affinity with 6CHZ  
Figure 3: 2D Structure of 3a.4,5,6,7,7a-hexahydro-4,7-methanoindene with 6CHZ  
Figure 4: 2D Structure of 4,7- methanon-1H-indene with 6CHZ  
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Figure 5: 2D Structure of Squalene with 6CHZ  
2d Structure of Best Compound With 4a2j  
Figure 6: 2D Structure of 3a.4,5,6,7,7a-hexahydro-4,7-methanoindene with 4A2J  
ADMET analysis result of the best phytocompounds  
Figure 7: ADMET result of 3a.4,5,6,7,7a-hexahydro-4,7-methanoindene  
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Figure 8: ADMET result of 4,7- methanon-1H-indene  
Figure 9: ADMET result of Squalene  
DISCUSSION  
The present study evaluated seven phytochemicals derived from Hyptis verticillata for their potential interactions  
with estrogen receptor alpha (ERα; PDB ID: 6CHZ) and progesterone receptor (PR; PDB ID: 4A2J) through  
molecular docking and ADMET profiling. The results provide mechanistic insight into their possible anti-breast  
cancer activity, particularly in hormone-dependent and endocrine-resistant disease contexts.  
Drug-Likeness Evaluation  
Drug-likeness screening using Lipinski, Veber, Ghose, Egan, and Muegge filters revealed that 9,12,15-  
octadecatrien-1-ol and 1-fluorodecane satisfied most physicochemical parameters for oral bioavailability. These  
compounds exhibited optimal molecular weight, hydrogen bond donor/acceptor count, and lipophilicity profiles  
within acceptable ranges (Lipinski et al., 2001). The results suggest that these molecules possess favorable  
pharmacokinetic attributes that could support systemic delivery and metabolic stability, aligning with findings  
that early drug-likeness screening reduces late-stage attrition (Eberhardt et al., 2021).  
However, several compounds, including squalene and R-R,R-E-trans-Phytol, violated multiple rules, likely due  
to high hydrophobicity and molecular size. Despite this, such lipophilic molecules often exhibit strong membrane  
affinity and may act as allosteric modulators or bioenhancers in complex biological systems (Patel et al., 2022).  
Hence, while not ideal as oral drugs, they could serve as scaffolds for optimization.  
Molecular Docking Analysis  
Docking scores across the ligand library ranged from −4.5 to −6.9 kcal/mol, indicating variable binding affinity  
for ERα (6CHZ) and PR (4A2J). Among these, squalene (−6.9 kcal/mol with ERα) and 4,7-methanon-1H-indene  
(−6.4 kcal/mol with both ERα and PR) emerged as the most potent binders. The comparable affinities across  
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both receptor targets suggest that H. verticillata phytochemicals may exhibit dual modulatory activity—a  
desirable trait given the crosstalk between ERα and PR signaling in luminal breast cancers (Estrogen Receptor  
Signaling in Breast Cancer, 2023). This crosstalk has been implicated in transcriptional reprogramming and  
therapeutic resistance, implying that compounds capable of influencing both receptors could offer a strategic  
advantage (Genome-wide Crosstalk between Steroid Receptors in Breast and Prostate Cancers, 2021). Squalene,  
a triterpenoid hydrocarbon, showed the strongest ERα interaction, consistent with previous evidence of its  
chemopreventive and antioxidant roles in breast and colon cancers (Kamal-Eldin & Appelqvist, 2020). Its  
binding pose likely involves hydrophobic interactions within the ERα ligand-binding domain, possibly  
stabilizing an antagonist-like conformation that impairs coactivator recruitment (Shiau et al., 1998).  
Similarly, 4,7-methanon-1H-indene and 3a,4,5,6,7,7a-hexahydro-4,7-methanoindene displayed stable docking  
conformations across both ERα and PR, suggesting structural adaptability and favorable steric compatibility  
with the hydrophobic core of steroid receptor binding cavities. Their ring systems likely mimic the steroidal  
skeleton, allowing effective π–alkyl and van der Waals interactions that stabilize receptor binding (Lusher et al.,  
2012).  
Comparative Binding Insights  
The docking affinity of squalene (−6.9 kcal/mol) against ERα-Y537S—a clinically relevant mutant associated  
with ligand-independent activation—implies potential activity against endocrine-resistant breast cancer  
phenotypes. Y537S mutation stabilizes the receptor’s active state, reducing sensitivity to tamoxifen and  
fulvestrant (Fanning et al., 2016). Thus, phytocompounds capable of maintaining favorable binding energies in  
this context could provide alternative scaffolds for designing resistance-competent SERMs or SERDs.  
For PR (4A2J), 4,7-methanon-1H-indene showed comparable affinity (−6.4 kcal/mol), indicating a potential to  
interfere with PR-mediated transcriptional programs. Given recent findings that PR signaling supports immune  
evasion through MHC-I downregulation (Progesterone Receptor–Dependent Downregulation of MHC Class I,  
2025), PR modulators from H. verticillata could indirectly enhance tumor immunogenicity.  
ADMET Prediction  
ADMET profiling of lead compounds demonstrated acceptable intestinal absorption, low hepatotoxicity  
potential, and non-carcinogenicity for 3a,4,5,6,7,7a-hexahydro-4,7-methanoindene and 4,7-methanon-1H-  
indene. While squalene showed limited solubility and potential for high lipophilicity-related bioaccumulation,  
such features could be optimized through structural derivatization or nanoparticle encapsulation for improved  
delivery (Nguyen et al., 2022).  
Biological and Therapeutic Implications  
Collectively, the findings highlight the pharmacological promise of H. verticillata constituents as modulators of  
hormone receptor activity in breast cancer. Compounds such as squalene and 4,7-methanon-1H-indene exhibit  
structural features consistent with receptor antagonism, aligning with prior reports of H. verticillata extracts  
exhibiting cytotoxic and anti-inflammatory activities (Biological Activity and Chemical Composition of Hyptis  
verticillata, 2005). The results suggest that rational modification of these scaffolds may yield more potent  
analogues targeting ERα-Y537S and PR, thus contributing to the development of multi-receptor-directed  
therapeutics capable of mitigating resistance in hormone-dependent breast cancers. However, further molecular  
dynamics simulations and in vitro receptor-binding assays are warranted to confirm binding stability, assess  
conformational dynamics, and validate biological activity.  
CONCLUSION  
This in silico study provides valuable insights into the potential of Hyptis verticillata-derived phytochemicals as  
dual modulators of estrogen receptor alpha (ERα) and progesterone receptor (PR) in hormone-dependent breast  
cancer. Among the analyzed compounds, squalene, 4,7-methanon-1H-indene, and 3a,4,5,6,7,7a-hexahydro-4,7-  
methanoindene demonstrated the most favorable binding affinities and pharmacokinetic properties, suggesting  
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their suitability as lead candidates for further drug development. Their ability to interact stably within the  
receptor ligand-binding domains implies a potential to modulate receptor signaling pathways that drive  
proliferation and endocrine resistance.  
The findings underscore the therapeutic relevance of natural compounds in addressing the limitations of current  
endocrine therapies, particularly those targeting ERα mutations such as Y537S that confer ligand-independent  
activity. Moreover, the dual targeting of ERα and PR may offer a synergistic advantage by disrupting receptor  
crosstalk mechanisms implicated in tumor progression and immune evasion. While these computational results  
are promising, experimental validation through molecular dynamics simulations, in vitro cytotoxicity assays,  
and receptor-binding studies is necessary to confirm biological efficacy and safety. Overall, this study establishes  
a scientific foundation for the exploration of H. verticillata phytochemicals as potential multitargeted agents in  
the management of hormone receptor–positive and endocrine-resistant breast cancers.  
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