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Identifying novel small molecule antagonists for mLST8 protein using computational approaches
Tuleshwori Devi Sapam1, Anbumani Velmurugan Ilavarasi1, Bhagath Kumar Palaka1
1a Centre for Bioinformatics, School of Life Sciences , Pondicherry University , Puducherry , India.
Journal of Receptor and Signal Transduction Research
|October 19, 2017
Summary
Targeting the mammalian lethal with SEC13 protein 8 (mLST8) shows promise for treating colon and prostate cancers. In silico drug design identified potent mLST8 antagonists, potentially hindering tumor progression.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Mammalian lethal with SEC13 protein 8 (mLST8) is crucial for the mammalian target of rapamycin (mTOR) signaling pathway.
- Overexpression of mLST8 is linked to tumor progression in human colon and prostate cancers via mTORC1/2 activation.
Purpose of the Study:
- To explore mLST8 as a therapeutic target for colon and prostate cancers.
- To identify potential drug candidates using in silico structure-based drug design.
Main Methods:
- Comparative binding pattern analysis of BINOL, SCF-12, and analogs within the mLST8 protein cavity.
- In silico ADME and binding energy calculations.
- Molecular dynamics (MD) simulations and free energy landscape (FEL) analysis.
Main Results:
- Five compounds exhibited favorable Glide (G) scores, with Asn132 and Gln225 identified as key binding residues.
- MD simulations and FEL elucidated the binding mechanism.
- Ligands ZINC01765622, ZINC62723702, and ZINC02576980 were identified as promising mLST8 antagonists.
Conclusions:
- Targeting mLST8 presents a viable therapeutic strategy against tumor progression in colon and prostate cancers.
- The identified potent hits demonstrate the potential to inhibit mLST8 activity and hinder cancer growth.