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In Silico Identification of Lepiotaprocerin C as a Promising PIM-1 Kinase Inhibitor: An Integrated Docking, Molecular
Keshava Ks1, Faten Qais Ibraheem2, Shankar Thapa3
1Department of Pharmacology, GM Institute of Pharmaceutical Sciences and Research, Davangere, India.
Abstract:
Proviral Integration site for Moloney murine leukemia virus-1 (PIM-1) kinase, a serine/threonine kinase overexpressed in various malignancies, plays a critical role in promoting cell survival and proliferation, making it a promising target for anticancer therapy. This study employed an integrated in silico approach to evaluate Lepiotaprocerin derivatives (A to L) from Macrolepiota procera as potential PIM-1 inhibitors. Molecular docking of 12 Lepiotaprocerins revealed Lepiotaprocerin C as the most potent compound, exhibiting superior binding affinity (-11.4 kcal/mol) compared with the reference inhibitor AZD1208. Binding site validation using CASTp, PrankWeb, and blind docking confirmed the ATP-binding pocket as the active cavity. The Lepiotaprocerin C-PIM-1 complex demonstrated enhanced stability during 200 ns molecular dynamics simulations, maintaining low RMSD and strong hydrogen-bond interactions, supported by a favorable Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) binding free energy (-22.0 ± 2.1 kcal/mol). Based on quantitative structure activity relationship (QSAR) analysis, the calculated pIC50 value of Lepiotaprocerin C was 8.67. QSAR modeling (R 2 = .74, Q 2 = 0.90) confirmed robust predictive capacity, while absorption, distribution, metabolism, and elimination and PerMM analysis indicated favorable pharmacokinetic and permeability profiles. Prediction of Activity Spectra for Substances and toxicity predictions further revealed high antineoplastic potential (Pa = 0.881) and a nontoxic safety profile. These results highlight Lepiotaprocerin C as a promising, stable, and safe inhibitor of PIM-1 kinase, warranting further in vitro and in vivo validation for potential anticancer drug development.
Insights
Lepiotaprocerin C from Macrolepiota procera shows promise as a PIM-1 kinase inhibitor for cancer therapy. Computational studies confirm its potent binding, stability, and favorable safety profile, suggesting potential for drug development.
Area of Science:
- Computational chemistry and drug discovery
- Molecular modeling and simulation
- Pharmacology and medicinal chemistry
Background:
- Proviral Integration site for Moloney murine leukemia virus-1 (PIM-1) kinase is a serine/threonine kinase crucial for cell survival and proliferation.
- PIM-1 kinase is overexpressed in various malignancies, making it a significant therapeutic target for anticancer drug development.
- Natural compounds offer a rich source for identifying novel therapeutic agents.
Purpose of the Study:
- To evaluate Lepiotaprocerin derivatives from Macrolepiota procera as potential inhibitors of PIM-1 kinase using an integrated in silico approach.
- To identify the most potent Lepiotaprocerin derivative and assess its binding affinity, stability, and pharmacokinetic properties.
- To predict the antineoplastic potential and safety profile of the lead compound.
Main Methods:
- Molecular docking was performed on 12 Lepiotaprocerin derivatives against PIM-1 kinase.
- Binding site validation utilized CASTp, PrankWeb, and blind docking.
- Molecular dynamics simulations, MM/PBSA, QSAR analysis, ADMET, PerMM, and toxicity predictions were employed.
Main Results:
- Lepiotaprocerin C exhibited the highest binding affinity (-11.4 kcal/mol) to the PIM-1 ATP-binding pocket, surpassing the reference inhibitor.
- Molecular dynamics simulations confirmed the stability of the Lepiotaprocerin C-PIM-1 complex, with favorable binding free energy (-22.0 ± 2.1 kcal/mol).
- QSAR modeling predicted a potent activity (pIC50 = 8.67) and favorable pharmacokinetic/safety profiles, with high antineoplastic potential (Pa = 0.881).
Conclusions:
- Lepiotaprocerin C is identified as a potent, stable, and safe inhibitor of PIM-1 kinase.
- The compound demonstrates significant potential for development as an anticancer therapeutic agent.
- Further in vitro and in vivo studies are warranted to validate its efficacy and safety for clinical application.
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