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Lakshmanan Loganathan1, Karthikeyan Muthusamy1, John Marshal Jayaraj1
1a Department of Bioinformatics , Alagappa University , Karaikudi , India.
Abstract:
The Wnt/β-catenin pathway plays an important regulatory role in cancer signaling and cell regenerative mechanisms. Its suppression has long been considered as an important challenge of anticancer treatment and management. The poly(ADP-ribose) polymerase (PARP) family represented as a new class of therapeutic targets with diverse potential disease indications. Tankyrase (TNKS) is considered to be a potential target for the intervention of various cancers. The main objective of the work is to explore the molecular and quantum mechanics of the drug-like compounds and to identify the potential inhibitors for TNKS protein using the structure and ligand-based virtual screening from several databases and to explore the binding pocket and interactions of active residues. The screened compounds were further filtered using binding-free energy calculation and molecular dynamics simulation studies. The results have provided a strong molecular knowledge of TNKS and offered top hit potent inhibitors. The identified lead compounds LC_40781, LC_40777, LC_39767, LC_8346, NCI_682438, and NCI_721141 were observed to have potent activity against TNKS protein. The hydrogen bonding of compounds with Asp1198, His1201, Tyr1203 in TNKS1 and Gly1032, Ser1068 in TNKS2 are the key interactions plays a major role in binding energy. Therefore, the outcome of the study would help for further validation and provides valuable information to guide the future TNKS-specific inhibitor designing. Communicated by Ramaswamy H. Sarma.
Insights
Researchers identified potent tankyrase (TNKS) inhibitors using virtual screening and molecular dynamics. These compounds show promise for developing new anticancer therapies targeting the Wnt/β-catenin pathway.
Area of Science:
- Oncology
- Molecular Biology
- Computational Chemistry
Background:
- The Wnt/β-catenin pathway is crucial in cancer and regeneration, but its suppression is challenging for cancer treatment.
- Poly(ADP-ribose) polymerase (PARP) enzymes, including tankyrase (TNKS), are emerging therapeutic targets for various diseases.
- TNKS is a key target for intervening in multiple cancer types.
Purpose of the Study:
- To explore molecular and quantum mechanics of drug-like compounds.
- To identify potential tankyrase (TNKS) inhibitors using virtual screening.
- To analyze the binding pocket and interactions of active residues within TNKS.
Main Methods:
- Structure and ligand-based virtual screening across multiple databases.
- Binding-free energy calculations for compound filtering.
- Molecular dynamics simulations to assess compound stability and interactions.
Main Results:
- Identified potent TNKS inhibitors, including LC_40781, LC_40777, LC_39767, LC_8346, NCI_682438, and NCI_721141.
- Elucidated key interactions, such as hydrogen bonding with Asp1198, His1201, Tyr1203 (TNKS1) and Gly1032, Ser1068 (TNKS2).
- Provided molecular insights into TNKS function and inhibitor binding.
Conclusions:
- The study offers valuable molecular knowledge of TNKS.
- Identified lead compounds demonstrate potent activity against TNKS.
- Findings guide future design of TNKS-specific inhibitors for cancer therapy.