In-silico study of active phytochemicals and molecular mechanism of Hydrocotyle javanica Thunb.in treating MDR enterobacterial infection
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Debasmita Paul1, Megha Ghosh2, Manab Mandal3
1Department of Botany, Jogamaya Devi College, Kolkata, 700026, West Bengal, India.
Abstract:
Enterobacterial infections being severe, with a high mortality rate, particularly affecting ICU patients, and 80% newborns. These infections have multifactorial multi-drug resistance (MDR) mechanisms, which frequently causes current antibiotic therapies to fail, mortality rate remains high, and creating an urgent need for alternative multi-targeted therapies, such as plant-derived compounds to restore clinical effectiveness. This study aims to discover novel anti enteric compounds in Hydrocotyle javanica Thunb. (H. javanica) belongs to Apiaceae family and understanding their interaction mechanism with enterobacterial infection targeted genes, using network pharmacology with in-silico docking and molecular dynamics simulation approaches. Four bioactive compounds as tetracosanoic acid, alpha-Amyrenyl acetate, stigmasterol glucoside, stigmasterol were identified as potential therapeutic agents. Most of the compounds exhibited favourable pharmacokinetic properties, complying with Lipinski's rule, with high bioavailability score 0.85 and non-toxic profiles. In-silico antibacterial prediction indicated both bacterial and bacteriostatic activities. A total of 53 common targets were identified with network analysis revealing key hub genes including HSD11B1, PTGS2,FDFT1,CYPHA1, and AKR1C2. Functional enrichment analysis showed significant involvement in immune and inflammatory pathways, particularly calcium signaling, MAPK signaling and reactive oxygen species related pathways. The docking result showed highest binding affinity, with stigmasterol showing highest score (-10.7 kcal/mol). A 100 ns molecular dynamics simulation further confirmed the stability of the stigmasterol-protein complex, with stable RMSD values 1-2 Å, low RMSF fluctuations and consistent hydrogen bonding, indicating sustained structural integrity. The present study highlights that phytocompounds from Hydrocotyle javanica exhibit significant binding affinity toward key enterobacterial targets, along with favorable ADME and toxicity profiles. These findings suggest their potential as promising lead molecules for anti-enterobacterial drug development, warranting further experimental validation.
Insights
Hydrocotyle javanica compounds show potential against multi-drug resistant enterobacterial infections. Stigmasterol demonstrated strong binding affinity, suggesting a promising new avenue for developing effective anti-enterobacterial therapies.
Area of Science:
- Phytochemistry
- Computational Biology
- Pharmacology
Background:
- Enterobacterial infections pose a significant threat, especially to ICU patients and newborns, due to high mortality and multi-drug resistance (MDR).
- Existing antibiotic therapies often fail against MDR strains, necessitating the development of novel, multi-targeted therapeutic strategies.
- Plant-derived compounds are being explored as alternative treatments to overcome antibiotic resistance and restore clinical effectiveness.
Purpose of the Study:
- To identify novel anti-enterobacterial compounds from Hydrocotyle javanica (H. javanica).
- To elucidate the interaction mechanisms of these compounds with enterobacterial target genes using network pharmacology.
- To evaluate the therapeutic potential of identified compounds through in-silico docking and molecular dynamics simulations.
Main Methods:
- Network pharmacology was employed to identify common targets between H. javanica compounds and enterobacterial infections.
- In-silico molecular docking was performed to assess the binding affinity of identified compounds to key protein targets.
- Molecular dynamics simulations were conducted to validate the stability of compound-protein complexes.
Main Results:
- Four bioactive compounds, including stigmasterol, were identified from H. javanica with favorable pharmacokinetic and non-toxic profiles.
- Network analysis revealed key hub genes (HSD11B1, PTGS2, FDFT1, CYPHA1, AKR1C2) involved in inflammatory and immune pathways.
- Stigmasterol exhibited the highest binding affinity (-10.7 kcal/mol) and formed stable complexes with target proteins, confirmed by molecular dynamics simulations.
Conclusions:
- Phytocompounds from H. javanica demonstrate significant potential as anti-enterobacterial agents.
- Stigmasterol shows promising efficacy against key enterobacterial targets with favorable ADME and toxicity profiles.
- These findings support the development of H. javanica-derived compounds as novel lead molecules for anti-enterobacterial drug discovery.
