Structure-based pharmacophore modeling, virtual screening and simulation studies for the identification of potent
Mala Sharma1, Neha Sharma2, Mohd Muddassir3
1Department of Biosciences, Integral University, Lucknow, India.
Abstract:
Cyclin-dependent kinases are of critical importance in directing various cell cycle phases making them as potential tumor targets. Cyclin-dependent kinase 2 (CDK2) in particular plays a significant part during cell cycle events and its imbalance roots out tumorogenic environment. Herein, we built a structure-based pharmacophore model complementing the ATP pocket site of CDK2 with four pharmacophoric features, using a series of structures obtained from cluster analysis during MD simulation assessment. This was followed by its validation and further database screening against Taiwan indigenous plants database (5284 compounds). The screened compounds were subjected toward Lipinski's rule (RO5) and ADMET filter followed by docking analysis and simulation study. In filtering hits (10 compounds) via molecular docking against CDK2, Schinilenol with -8.1 kcal/mol fetched out as a best lead phytoinhibitor in the presence of standard drug (Dinaciclib). Additionally, pharmacophore mapping analysis also indicated relative fit values of dinaciclib and schinilenol as 2.37 and 2.31, respectively. Optimization, flexibility prediction and the stability of CDK2 in complex with the ligands were also ascertained by means of molecular dynamics for 50 ns, which further proposed schinilenol having better binding stability than dinaciclib with RMSD values ranging from 0.31 to 0.34 nm. Reactivity site, biological activity detection and cardiotoxicity assessment also proposed schinilenol as a better phytolead inhibitor than the existing dinaciclib. Abbreviations: CDK2: Cyclin dependent kinase2; ATP: Adenosine triphosphate; MD: Molecular dynamics, RO5: Rule of five; ADMET: Absorption, distribution, metabolism, and excretion; RMSD: Root mean square deviation; DS: Discovery Studio; SOM: Site of metabolism; RBPM: receptor based pharmacophore model; TIP: Schinilenol; hERG: human Ether-à-go-go - Related GeneCommunicated by Ramaswamy H. Sarma.
Insights
Researchers identified Schinilenol from Taiwan indigenous plants as a potent inhibitor of Cyclin-dependent kinase 2 (CDK2), a key target in cancer therapy. Molecular modeling and simulations confirmed its superior binding stability and potential as a novel anti-cancer phytolead compared to Dinaciclib.
Area of Science:
- Medicinal Chemistry
- Computational Drug Discovery
- Molecular Pharmacology
Background:
- Cyclin-dependent kinases (CDKs) are crucial regulators of the cell cycle and are implicated in oncogenesis.
- Cyclin-dependent kinase 2 (CDK2) is a significant target for anti-cancer drug development due to its role in cell cycle progression.
- Targeting CDK2 imbalances offers a promising strategy for developing novel tumor therapies.
Purpose of the Study:
- To develop a structure-based pharmacophore model for Cyclin-dependent kinase 2 (CDK2).
- To screen Taiwan indigenous plant databases for potential CDK2 inhibitors.
- To evaluate the efficacy and binding stability of identified natural compounds against CDK2.
Main Methods:
- Construction and validation of a structure-based pharmacophore model for CDK2 using molecular dynamics simulations.
- Database screening of Taiwan indigenous plants (5284 compounds) followed by Lipinski's Rule of Five (RO5) and ADMET filtering.
- Molecular docking, pharmacophore mapping, and 50 ns molecular dynamics (MD) simulations to assess binding affinity and stability.
Main Results:
- Schinilenol was identified as the best lead phytoinhibitor, exhibiting a binding energy of -8.1 kcal/mol, surpassing the standard drug Dinaciclib.
- Pharmacophore mapping showed comparable fit values for Schinilenol (2.31) and Dinaciclib (2.37).
- Molecular dynamics simulations indicated superior binding stability for Schinilenol with lower Root Mean Square Deviation (RMSD) values (0.31–0.34 nm) compared to Dinaciclib.
Conclusions:
- Schinilenol demonstrates significant potential as a potent and stable phytolead inhibitor of CDK2.
- Its favorable binding characteristics and predicted safety profile suggest it as a promising candidate for further anti-cancer drug development.
- This study highlights the value of indigenous plant resources in discovering novel therapeutic agents targeting cell cycle regulators.
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