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Target-based virtual screening and molecular interaction studies for lead identification of natural olive compounds
Arabinda Ghosh1, Dipanwita Chakraborty2, Nobendu Mukerjee3
1Microbiology Division, Department of Botany, Gauhati University, Guwahati, Assam, India.
Abstract:
Glioblastoma multiforme, a rare traumatic brain disorder, is at the research climax for its uncontrolled growth leading to a catastrophic outcome. Throwing light on the target-based virtual screening of drugs using natural phytocompounds is a striking cornerstone in glioblastoma-based drug discovery, accelerating with leaps and bounds. This project aims to develop promising lead compounds against glioblastoma brain cancer using OliveNet™, an open-source database. In this pursuit, our rationale for selecting molecules was based on their capability to pass through the blood-brain barrier. Out of 51 derivative molecules from flavonoids and polyphenols, 17 molecules were screened out bearing the best ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, alongside fulfilling our rationale of lead selection. Two polyphenols, 3,4,5-trimethoxybenzoic acid and 4-ethyl guaiacol, have binding affinity for the antioxidant flavonoid luteolin of -5.1 and -4.3 kcal/mol, respectively. According to docking studies, the residues ASN1960, ASN1966, ASN1960, PHE1984, TYR1896, VAL1911, and LYS1966 make both polar and nonpolar interactions with 3,4,5-trimethoxybenzoic acid and 4-ethylguanidine, respectively. LD50 values of toxicity screening using TOX Pro brought to limelight the excellent safety profile of polyphenols and flavonoids. Furthermore, studies using in silico cytotoxicity prediction and molecular modelling have decisively shown that these polyphenols are likely to be effective brain cancer inhibitors and promising future lead candidates against glioblastoma multiforme.
Insights
Natural compounds show promise for glioblastoma treatment. Researchers identified 17 flavonoid and polyphenol molecules with good safety and drug-like properties, including two polyphenols that effectively bind to a key antioxidant, suggesting potential as brain cancer inhibitors.
Area of Science:
- Pharmacology and Computational Chemistry
- Oncology
- Natural Product Chemistry
Background:
- Glioblastoma multiforme is an aggressive brain cancer with poor outcomes.
- Target-based virtual screening of natural compounds offers a promising avenue for glioblastoma drug discovery.
- Developing drugs that can cross the blood-brain barrier is crucial for treating brain cancers.
Purpose of the Study:
- To identify potential lead compounds for glioblastoma treatment using natural phytocompounds.
- To screen molecules for favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties.
- To evaluate the blood-brain barrier penetration capability of selected compounds.
Main Methods:
- Utilized OliveNet™, an open-source database, for virtual screening of 51 flavonoid and polyphenol derivatives.
- Screened 17 molecules based on ADMET properties and blood-brain barrier permeability.
- Performed molecular docking studies to assess binding affinity with luteolin and identified key interacting residues.
- Conducted in silico toxicity screening using TOX Pro and cytotoxicity prediction.
Main Results:
- 17 out of 51 derivative molecules exhibited desirable ADMET properties and met lead selection criteria.
- Two polyphenols, 3,4,5-trimethoxybenzoic acid and 4-ethyl guaiacol, showed significant binding affinity to luteolin (-5.1 and -4.3 kcal/mol).
- Docking studies revealed specific polar and nonpolar interactions between the compounds and target residues.
- Toxicity screening indicated an excellent safety profile for the selected polyphenols and flavonoids.
Conclusions:
- The identified polyphenols and flavonoids demonstrate potential as effective inhibitors of glioblastoma multiforme.
- These compounds represent promising future lead candidates for glioblastoma drug development.
- In silico studies support the efficacy and safety of these natural compounds against brain cancer.
