Structure-guided discovery of marine natural products as glucokinase activators for type 2 diabetes mellitus: A computational perspective.
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| Format: | Artículo científico |
| Langue: | en |
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Journal of molecular graphics & modelling
2026
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| _version_ | 1868266144179159040 |
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| author | Krishnakumar, Heyram Jayaraman, Manikandan Prabhu, Dhamodharan Jeyakanthan, Jeyaraman |
| author_facet | Krishnakumar, Heyram Jayaraman, Manikandan Prabhu, Dhamodharan Jeyakanthan, Jeyaraman Krishnakumar, Heyram Jayaraman, Manikandan Prabhu, Dhamodharan Jeyakanthan, Jeyaraman |
| collection | PubMed - marine biology |
| contents | Structure-guided discovery of marine natural products as glucokinase activators for type 2 diabetes mellitus: A computational perspective. Krishnakumar, Heyram Jayaraman, Manikandan Prabhu, Dhamodharan Jeyakanthan, Jeyaraman Glucokinase Diabetes Mellitus, Type 2 Humans Biological Products Molecular Docking Simulation Hypoglycemic Agents Drug Discovery Molecular Dynamics Simulation Enzyme Activators Aquatic Organisms Protein Binding Ligands Structure-Activity Relationship Enzyme Activation Diabetes is a prevalent metabolic disorder and the ninth leading cause of mortality worldwide. Despite the availability of effective hypoglycemic agents, there remains an urgent need for more potent therapeutics with minimal adverse effects. Targeting key metabolic regulators, such as enzymes, transporters, and receptors, offers promising avenues for drug discovery. Glucokinase (GCK), a pivotal enzyme in glucose metabolism, catalyzes the conversion of glucose into glucose-6-phosphate and functions as a glucose sensor, making it a highly attractive therapeutic target for Type 2 Diabetes Mellitus (T2DM). This study investigates the potential of marine-derived bioactive compounds as GCK activators. Structure-based virtual screening (SBVS) of approximately 32,000 marine natural products (MNPs) against human GCK (PDB ID: 1V4S) identified four promising candidates: CMNPD6570, CMNPD5231, SWMDBB001, and SWMDBB004. These MNPs exhibited favorable binding affinity scores (ranging from -8.80 to -12.62 kcal/mol) and formed key interactions with critical residues, including Tyr61, Arg63, Thr65, Tyr214, and Tyr215. Additionally, MM-GBSA binding free energy calculations (-89.54 to -115.66 kcal/mol) and MM-PBSA analysis (-93.05 to -306.18 kJ/mol) further supported their strong binding affinity. Pharmacokinetic and toxicity predictions indicated favorable drug-like properties for all identified MNPs. All-atom molecular dynamics (MD) simulations for 300 ns demonstrated enhanced structural stability of these compounds compared to the native ligand. Notably, CMNPD6570 and SWMDBB004 exhibited stable GCK binding, with low RMSD values and minimal fluctuations in key residues. Furthermore, free energy landscape (FEL) analysis using principal component (PC) projections confirmed the stability of these interactions. Overall, these findings underscore the potential of marine-derived bioactive compounds as novel GCK activators, laying a strong foundation for future experimental validation and the development of therapeutics for T2DM. |
| format | Artículo científico |
| id | pubmed_41056674 |
| institution | PubMed |
| language | en |
| publishDate | 2026 |
| publisher | Journal of molecular graphics & modelling |
| record_format | pubmed |
| spellingShingle | Structure-guided discovery of marine natural products as glucokinase activators for type 2 diabetes mellitus: A computational perspective. Krishnakumar, Heyram Jayaraman, Manikandan Prabhu, Dhamodharan Jeyakanthan, Jeyaraman Glucokinase Diabetes Mellitus, Type 2 Humans Biological Products Molecular Docking Simulation Hypoglycemic Agents Drug Discovery Molecular Dynamics Simulation Enzyme Activators Aquatic Organisms Protein Binding Ligands Structure-Activity Relationship Enzyme Activation Structure-guided discovery of marine natural products as glucokinase activators for type 2 diabetes mellitus: A computational perspective. Krishnakumar, Heyram Jayaraman, Manikandan Prabhu, Dhamodharan Jeyakanthan, Jeyaraman Glucokinase Diabetes Mellitus, Type 2 Humans Biological Products Molecular Docking Simulation Hypoglycemic Agents Drug Discovery Molecular Dynamics Simulation Enzyme Activators Aquatic Organisms Protein Binding Ligands Structure-Activity Relationship Enzyme Activation Diabetes is a prevalent metabolic disorder and the ninth leading cause of mortality worldwide. Despite the availability of effective hypoglycemic agents, there remains an urgent need for more potent therapeutics with minimal adverse effects. Targeting key metabolic regulators, such as enzymes, transporters, and receptors, offers promising avenues for drug discovery. Glucokinase (GCK), a pivotal enzyme in glucose metabolism, catalyzes the conversion of glucose into glucose-6-phosphate and functions as a glucose sensor, making it a highly attractive therapeutic target for Type 2 Diabetes Mellitus (T2DM). This study investigates the potential of marine-derived bioactive compounds as GCK activators. Structure-based virtual screening (SBVS) of approximately 32,000 marine natural products (MNPs) against human GCK (PDB ID: 1V4S) identified four promising candidates: CMNPD6570, CMNPD5231, SWMDBB001, and SWMDBB004. These MNPs exhibited favorable binding affinity scores (ranging from -8.80 to -12.62 kcal/mol) and formed key interactions with critical residues, including Tyr61, Arg63, Thr65, Tyr214, and Tyr215. Additionally, MM-GBSA binding free energy calculations (-89.54 to -115.66 kcal/mol) and MM-PBSA analysis (-93.05 to -306.18 kJ/mol) further supported their strong binding affinity. Pharmacokinetic and toxicity predictions indicated favorable drug-like properties for all identified MNPs. All-atom molecular dynamics (MD) simulations for 300 ns demonstrated enhanced structural stability of these compounds compared to the native ligand. Notably, CMNPD6570 and SWMDBB004 exhibited stable GCK binding, with low RMSD values and minimal fluctuations in key residues. Furthermore, free energy landscape (FEL) analysis using principal component (PC) projections confirmed the stability of these interactions. Overall, these findings underscore the potential of marine-derived bioactive compounds as novel GCK activators, laying a strong foundation for future experimental validation and the development of therapeutics for T2DM. |
| title | Structure-guided discovery of marine natural products as glucokinase activators for type 2 diabetes mellitus: A computational perspective. |
| topic | Glucokinase Diabetes Mellitus, Type 2 Humans Biological Products Molecular Docking Simulation Hypoglycemic Agents Drug Discovery Molecular Dynamics Simulation Enzyme Activators Aquatic Organisms Protein Binding Ligands Structure-Activity Relationship Enzyme Activation |
| url | https://pubmed.ncbi.nlm.nih.gov/41056674/ |