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Updated: Sep 27, 2025
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Identification of novel protein kinase C-βII inhibitors: virtual screening, molecular docking and molecular dynamics
Bharat Kumar Reddy Sanapalli1, Vidyasrilekha Yele2, Lalji Baldaniya3
1Department of Pharmacology, Faculty of Pharmacy, Marwadi University, Rajkot, Gujarat, 360003, India. bharathsanapalli@yahoo.in.
Abstract:
Diabetic wounds (DWs) are the major end-stage manifestation encountered in diabetic patients. The two major pathways involved in the pathogenesis of DW are impaired angiogenesis and unnecessary NETosis, which are regulated by a common enzyme called protein kinase C (PKC)-βII. PKC-βII is a conventional isoform of PKC family that can be activated by calcium and diacylglycerol. PKC-βII possesses a specific expression profile and plays a distinct role in various cellular and molecular functions. The pathogenic role of PKC-βII and its involvement in the impairment of wound healing suggested that PKC-βII plays a potential role in DW progression. Hence, there is a renewed interest in developing specific inhibitors of PKC-βII. In the present study, receptor-based virtual screening was performed for the identification of potential PKC-βII inhibitors using TimTec, Enamine, Zinc and Specs databases. A total of 595 candidate compounds were evaluated based on absorption, distribution, metabolism, excretion and toxicity, standard precision docking. Further, extra-precision docking and binding free energy calculations were carried out for top-ranked compounds. Based on Glide score and protein-ligand interactions, we have identified compound 1 as a potential inhibitor. Finally, molecular dynamics (MD) simulation was performed for top compound 1 using the Desmond module (Schrödinger suite) to identify the structural stability of the protein-ligand complex. Gratifyingly, MD trajectory analysis demonstrated the stable binding conformation of compound 1 with PKC-βII enzyme. In silico approaches incorporated in this study provide a set of new putative PKC-βII inhibitors which could be potential leads to develop DW therapeutics.
Insights
Researchers identified a potential new drug target for diabetic wounds by virtually screening compounds to find inhibitors of protein kinase C beta-II (PKC-βII). Compound 1 showed stable binding, offering a promising lead for developing diabetic wound therapeutics.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- Diabetic wounds (DWs) represent a significant complication in diabetes management.
- Impaired angiogenesis and excessive NETosis, regulated by protein kinase C beta-II (PKC-βII), are key factors in DW pathogenesis.
- Targeting PKC-βII is a promising strategy for developing novel therapeutics for diabetic wound healing.
Purpose of the Study:
- To identify potential inhibitors of PKC-βII using in silico methods.
- To evaluate the drug-likeness and binding affinity of candidate compounds.
- To assess the stability of the protein-ligand complex through molecular dynamics simulations.
Main Methods:
- Receptor-based virtual screening of multiple compound databases (TimTec, Enamine, Zinc, Specs).
- Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) prediction and standard/extra-precision docking.
- Binding free energy calculations and molecular dynamics (MD) simulations using the Desmond module.
Main Results:
- 595 candidate compounds were initially screened.
- Compound 1 was identified as a potential PKC-βII inhibitor based on docking scores and interactions.
- MD simulations confirmed the stable binding conformation of Compound 1 with the PKC-βII enzyme.
Conclusions:
- In silico approaches successfully identified novel putative inhibitors of PKC-βII.
- Compound 1 represents a promising lead compound for the development of therapeutics targeting diabetic wounds.
- This study highlights the utility of computational methods in drug discovery for complex diseases like diabetes.
