Exploring novel and potent molecules for disrupting DEPTOR-mTOR interaction through structure-steered screening,
Basit Amin Shah1, Shabir Ahmad Ganai1, Aabid M Koul1
1Department of Biotechnology, University of Kashmir, Srinagar, Jammu & Kashmir, India.
Abstract:
Dep domain containing mTOR interacting protein (DEPTOR) has critical implications in the development and progression of human malignancies. Increased expression of DEPTOR promotes the growth of tumor cells by inhibiting the mTORC1, which alleviates the negative feedback inhibition by mTORC1 downstream target S6Ks on PI3K/AKT pathway thereby promotes cell survival and prevents apoptosis. This clearly suggests that targetting DEPTOR-mTOR interactions through small molecules may prove as an effective strategy for circumventing distinct cancers. In this study, we employed a top-down approach for finding three novel molecules which may prove effective in disrupting Deptor-mTOR interaction. Following DEPTOR modelling and validation we performed grid-directed structure-based screening by specifying the residues of DEPTOR known to interact with mTOR. A library of 10,000 protein-protein disrupting molecules was screened against the defined region of DEPTOR. From the screened molecules, 30 molecules with highest binding affinity were chosen for molecular docking. Thirty (30) extra-precision molecular docking experiments and 30 molecular mechanics generalized born surface area (MMGBSA) assays were performed. Following this top 10 molecules in terms of binding affinity were selected and the interaction profile of their corresponding docked files was generated. The top three molecules were finally selected after taking all the three parameters including docking score, binding energy value and interaction profile into consideration. For atomistic insights regarding DEPTOR-topmost hit interactions, molecular dynamics was performed for 100 ns. This molecule after further evaluation may prove as promising candidate for anticancer therapy.Communicated by Ramaswamy H. Sarma.
Insights
Researchers identified three novel small molecules that disrupt the DEPTOR-mTOR interaction, a key driver in cancer progression. These molecules show promise as potential anticancer therapeutics by targeting tumor cell growth and survival pathways.
Area of Science:
- Biochemistry and Molecular Biology
- Oncology
- Drug Discovery
Background:
- DEPTOR (Dep domain containing mTOR interacting protein) is implicated in human malignancies.
- Elevated DEPTOR expression promotes tumor growth by inhibiting mTORC1, which impacts cell survival and apoptosis.
- Targeting DEPTOR-mTOR interactions is a potential anticancer strategy.
Purpose of the Study:
- To identify novel small molecules capable of disrupting the DEPTOR-mTOR interaction.
- To evaluate the potential of these molecules as anticancer therapeutics.
Main Methods:
- Employed a top-down computational approach including DEPTOR modeling and validation.
- Performed grid-directed structure-based screening of 10,000 protein-protein disrupting molecules.
- Utilized molecular docking, MMGBSA assays, and molecular dynamics simulations for analysis.
Main Results:
- Screened 10,000 molecules, leading to the selection of top candidates based on binding affinity and interaction profiles.
- Identified three novel molecules with high potential to disrupt DEPTOR-mTOR interaction.
- Molecular dynamics confirmed atomistic insights into DEPTOR-topmost hit interactions.
Conclusions:
- The study successfully identified three promising small molecules targeting the DEPTOR-mTOR interaction.
- These molecules represent potential candidates for further development in anticancer therapy.
- Disrupting DEPTOR-mTOR interaction is a viable strategy for cancer treatment.
