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Simulation studies, 3D QSAR and molecular docking on a point mutation of protein kinase B with flavonoids targeting
Suchitra Maheswari Ajjarapu1,2, Apoorv Tiwari1,3, Gohar Taj1
1Bioinformatics Sub-DIC, Department of Molecular Biology & Genetic Engineering, College of Basic Science and Humanities, Govind Ballabh Pant University of Agriculture and Technology, Pantnagar, Udham Singh Nagar, 263145, Uttarakhand, India.
Background:
Ovarian cancer is the world's dreaded disease and its prevalence is expanding globally. The study of integrated molecular networks is crucial for the basic mechanism of cancer cells and their progression. During the present investigation, we have examined different flavonoids that target protein kinases B (AKT1) protein which exerts their anticancer efficiency intriguing the role in cross-talk cell signalling, by metabolic processes through in-silico approaches.
Method:
Molecular dynamics simulation (MDS) was performed to analyze and evaluate the stability of the complexes under physiological conditions and the results were congruent with molecular docking. This investigation revealed the effect of a point mutation (W80R), considered based on their frequency of occurrence, with AKT1 protein.
Results:
The ligand with high docking scores and favourable behaviour on dynamic simulations are proposed as potential W80R inhibitors. A virtual screening analysis was performed with 12,000 flavonoids satisfying Lipinski's rule of five according to which drug-likeness is predicted based on its pharmacological and biological properties to be active and taken orally. The pharmacokinetic ADME (adsorption, digestion, metabolism, and excretion) studies featured drug-likeness. Subsequently, a statistically significant 3D-QSAR model of high correlation coefficient (R2) with 0.822 and cross-validation coefficient (Q2) with 0.6132 at 4 component PLS (partial least square) were used to verify the accuracy of the models. Taxifolin holds good interactions with the binding domain of W80R, highest Glide score of - 9.63 kcal/mol with OH of GLU234 and H bond ASP274 and LEU156 amino acid residues and one pi-cation interaction and one hydrophobic bond with LYS276.
Conclusion:
Natural compounds have always been a richest source of active compounds with a wide variety of structures, therefore, these compounds showed a special inspiration for medical chemists. The present study has aimed molecular docking and molecular dynamics simulation studies on taxifolin targeting W80R mutant protein of protein kinase B/serine- threonine kinase/AKT1 (EC:2.7.11.1) protein of ovarian cancer for designing therapeutic intervention. The expected result supported the molecular cause in a mutant form which resulted in a gain of ovarian cancer. Here we discussed validations computationally and yet experimental evaluation or in vivo studies are endorsed for further study. Several of these compounds should become the next marvels for early detection of ovarian cancer.
Insights
This study used computational methods to identify taxifolin as a potential inhibitor for a mutated AKT1 protein involved in ovarian cancer progression. Further experimental studies are recommended to validate these findings for early cancer detection.
Area of Science:
- Computational chemistry
- Molecular modeling
- Drug discovery
Background:
- Ovarian cancer is a growing global health concern.
- Understanding molecular networks is key to cancer progression.
- Targeting protein kinases like AKT1 is a strategy for anticancer drug development.
Purpose of the Study:
- To investigate flavonoids as potential inhibitors of the AKT1 protein in ovarian cancer.
- To explore the role of the W80R mutation in AKT1.
- To design therapeutic interventions using in-silico approaches.
Main Methods:
- Virtual screening of 12,000 flavonoids using Lipinski's rule of five.
- Molecular docking and molecular dynamics simulations (MDS).
- 3D-Quantitative Structure-Activity Relationship (3D-QSAR) modeling.
Main Results:
- Taxifolin showed high binding affinity and favorable interactions with the W80R mutant AKT1 protein.
- Molecular dynamics simulations confirmed the stability of taxifolin-W80R complexes.
- A 3D-QSAR model with high accuracy (R2=0.822, Q2=0.6132) was developed.
Conclusions:
- Taxifolin is a promising candidate for inhibiting W80R mutant AKT1.
- The study provides a computational basis for developing novel ovarian cancer therapeutics.
- Experimental validation is recommended for further development.
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