Bioactive plantaricins as potent anti-cancer drug candidates: double docking, molecular dynamics simulation and in vitro cytotoxicity analysis

Abstract

The medical community is desperate for a reliable source of medications to alleviate the severity of conventional cancer treatments and prevent secondary microbial infections in oncological patients. In this regard, plantaricins from lactic acid bacteria were explored as prospective drug candidates against known anti-cancer drug targets. Three plantaricins, JLA-9, GZ1-27 and BN, have a binding affinity of −8.8, −8.6 and −7.2 kcal/mol, respectively, with squalene synthase (SQS), a key molecule in lung cancer metastasis. All three plantaricins displayed analogous binding patterns as SQS inhibitors and generated hydrogen and hydrophobic interactions with ARG 47, ARG 188, PHE24, LEU183 and PRO292. Structural stability of docked complexes was validated using molecular dynamics simulation derived parameters such as RMSD, RMSF and radius of gyration. Based on MD simulation results, conformational changes and stabilities of docked SQS/plantaricin complexes with respect to the time frame were evaluated using machine learning (logistic regression algorithm). Double docking with SQS/matrix metalloproteinase MMP1 and PCA analysis revealed the potential of plantaricin JLA-9 as a multi-substrate inhibitor. Further, plantaricin JLA-9 induced a significant cytotoxic response against the lung carcinoma cell line (A549) in a dose and time dependent manner with inhibition concentration (IC₅₀) of 0.082 µg/ml after 48 h. However, plantaricin JLA-9 did not induce cytotoxicity in normal lung cells (L-132), as the IC₅₀ value was not obtained even at a higher dose of 0.8 µg/ml. In silico pharmacokinetic (ADMET) profile implies that plantaricin JLA-9 could be developed as new age anti-cancer therapeutic with a preference for parenteral administration.

Communicated by Ramaswamy H. Sarma

Keywords:

• Plantaricin
• squalene synthase
• pharmacokinetic
• molecular docking
• PCA
• MTT assay

Author’s contributions

Soumyadip Chakrobarty and Swarnava Garai: Study conception, data design, analysis and interpretation of results (Equal contribution). Arabinda Ghosh and Nobendu Mukerjee: Study of molecular dynamics simulation, cell culture analysis and data interpretation. Deeplina Das: Conceptualize, design, wet lab experiments and manuscript preparation

Data availability statement

The raw structural data of protein targets and ligands are available on PDB (https://www.rcsb.org/), Bactibase (http://bactibase.hammamilab.org/) and PubChem (https://pubchem.ncbi.nlm.nih.gov/), respectively. The authors confirm that the data (docking, modeling, pharmacokinetic, toxicity and simulation) supporting the findings of this study are available within the article.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethics approval

The work described has not been published before and contains original computational data. The manuscript is not under consideration for publication anywhere else. The publication has been approved by all co-authors.

Additional information

Funding

Departmental facilities and M. Tech Project funding of NIT Agartala.