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Published on: February 23, 2024
Molecular Docking studies of FKBP12-mTOR inhibitors using binding predictions
Arash Boroumand Nasr1, Deepika Ponnala1, Someshwar Rao Sagurthi2
1Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad - 500 016, India.
Unlabelled:
Mammalian target of rapamycin (mTOR) is a key regulator of cell growth, proliferation and angiogenesis. mTOR signaling is frequently hyper activated in a broad spectrum of human cancers thereby making it a potential drug target. The current drugs available have been successful in inhibiting the mTOR signaling, nevertheless, show low oral bioavailability and suboptimal solubility. Considering the narrow therapeutic window of the available inhibitors, through computational approaches, the present study pursues to identify a compound with optimal oral bioavailability and better solubility properties in addition ensuing high affinity between FKBP12 and FRB domain of mTOR. Current mTOR inhibitors; Everolimus, Temsirolimus Deforolimus and Echinomycin served as parent molecules for similarity search with a threshold of 95%. The query molecules and respective similar molecules were docked at the binding cleft of FKBP12 protein. Aided by MolDock algorithm, high affinity compounds against FKBP12 were retrieved. Patch Dock supervised protein-protein interactions were established between FRB domain of mTOR and ligand (query and similar) bound and free states of FKBP12. All the similar compounds thus retrieved showed better solubility properties and enabled better complex formation of mTOR and FKBP12. In particular Everolimus similar compound PubChem ID: 57284959 showed appreciable drugs like properties bestowed with better solubility higher oral bioavailability. In addition this compound brought about enhanced interaction between FKBP12 and FRB domain of mTOR. In the study, we report Everolimus similar compound PubChem ID: 57284959 to be potential inhibitor for mTOR pathway which can overcome the affinity and solubility concerns of current mTOR drugs.
Abbreviations:
mTOR - Mammalian Target of Rapamycin, FRB domain - FKBP12-rapamycin associated protein, FKBP12 - FK506-binding protein 12, OPLS - Optimized Potentials for Liquid Simulations, Akt - RAC-alpha serine/threonine-protein kinase, PI3K - phosphatidylinositide 3-kinases.
Insights
Researchers identified a novel compound, similar to Everolimus (PubChem ID: 57284959), that shows promise for inhibiting the mammalian target of rapamycin (mTOR) pathway. This compound exhibits improved solubility and oral bioavailability, addressing limitations of current mTOR inhibitors.
Area of Science:
- Oncology
- Pharmacology
- Computational Chemistry
Background:
- Mammalian target of rapamycin (mTOR) signaling is crucial for cell growth and proliferation.
- Hyperactivation of mTOR signaling is common in human cancers, making it a significant drug target.
- Existing mTOR inhibitors face challenges with low oral bioavailability and solubility.
Purpose of the Study:
- To identify novel compounds with improved oral bioavailability and solubility for mTOR inhibition using computational approaches.
- To find compounds with enhanced affinity for the FKBP12 and FRB domains of mTOR.
- To address the limitations of current mTOR inhibitors.
Main Methods:
- Similarity searching of current mTOR inhibitors (Everolimus, Temsirolimus, Deforolimus, Echinomycin) with a 95% threshold.
- Molecular docking of query and similar compounds to the FKBP12 binding cleft using the MolDock algorithm.
- Protein-protein interaction analysis using Patch Dock between mTOR's FRB domain and FKBP12-ligand complexes.
Main Results:
- Several similar compounds demonstrated better solubility and facilitated improved complex formation between mTOR and FKBP12.
- A compound similar to Everolimus (PubChem ID: 57284959) exhibited favorable drug-like properties, including enhanced solubility and oral bioavailability.
- This identified compound showed increased affinity and interaction between FKBP12 and the FRB domain of mTOR.
Conclusions:
- Everolimus-similar compound (PubChem ID: 57284959) is a potential mTOR pathway inhibitor.
- This compound may overcome the affinity and solubility issues associated with current mTOR drugs.
- Computational methods successfully identified a promising candidate for improved cancer therapy targeting the mTOR pathway.
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