Identifying novel small molecule antagonists for mLST8 protein using computational approaches

• Published in: Journal of receptors and signal transduction 2018-01, Vol.38 (1), p.1-11
• Main Authors: Sapam, Tuleshwori Devi, Velmurugan Ilavarasi, Anbumani, Palaka, Bhagath Kumar, Elumalai, Elakkiya, Kanika, Nirmala Devi, Ampasala, Dinakara Rao
• Format: Article
• Language: English
• Subjects: Carboxylic Acids - chemistry; Catalytic Domain - drug effects; Colon cancer; Colonic Neoplasms - drug therapy; Computer Simulation; Drug Design; free energy landscape; Humans; Male; Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors; Mechanistic Target of Rapamycin Complex 1 - chemistry; mLST8; molecular docking; Molecular Dynamics Simulation; molecular dynamics simulations; Molecular Targeted Therapy; mTOR; MTOR Associated Protein, LST8 Homolog - antagonists & inhibitors; MTOR Associated Protein, LST8 Homolog - chemistry; mTOR signaling pathway; Naphthalenes - chemistry; Naphthols - chemistry; Naphthols - pharmacology; prostate cancer; Prostatic Neoplasms - drug therapy; Protein Binding; Signal Transduction - drug effects
• ISSN: 1079-9893; 1532-4281
• DOI: 10.1080/10799893.2017.1387920

Mammalian lethal with SEC13 protein 8 (mLST8), is an indispensable protein subunit of mammalian target of rapamycin (mTOR) signaling pathway that interacts with the kinase domain of mTOR protein, thereby stabilizing its active site. Experimental studies reported the over expression of mLST8 in human colon and prostate cancers by activation of both mTORC1/2 complexes and subsequent downstream substrates leading to tumor progression. Considering its role, targeting mLST8 protein would be a therapeutic approach against tumor progression in colon and prostate cancers. Hence, using in silico structure based drug design approach, the comparative binding patterns of 1,1′-binapthyl-2,2′diol (BINOL), 1-(2-carboxynaphth-1yl)-2-naphthoic acid (SCF-12) and their analogs in the cavity of mLST8 were explored. ADME and binding energy calculations led to the identification of five compounds with favorable Glide (G) scores and implicated the importance of Asn132 and Gln225 as key binding residues. Molecular dynamics (MD) simulations and free energy landscape (FEL) approaches helped in elucidating the binding mechanism and suggested the possibility of ligands 1-3 namely, ZINC01765622, ZINC62723702 and ZINC02576980 to be promising antagonists for mLST8. Thus, this study substantiates the prospect of targeting mLST8 protein using potent hits which could hinder tumor progression in colon and prostate cancers.