Table 2.
The major biological functions of the DIA-DB protein targets, the docking cutoff score, and the total number of potential inhibitors identified for each target.
| Mode of Action | Protein Target | Function | PDB Code | Average Docking Score of Known Drugs (kcal/mol) | Docking Cutoff (kcal/mol) | Total Number of Potential Inhibitors |
|---|---|---|---|---|---|---|
| Regulation of insulin secretion and sensitivity | DPP4 | Degrades and inactivates glucagon-like peptide-1 that stimulates insulin secretion from pancreas [231] | 4A5S | −8.50 | −9.00 | 260 |
| FFAR1 | Binding of free fatty acids to receptor results in increased glucose-stimulated insulin secretion [232] | 4PHU | −10.00 | −10.50 | 6 | |
| HSD11B1 | Coverts inactive glucocorticoid precursors to active glucocorticoids; glucocorticoids counteract the effects of insulin [233] | 4K1L | −9.40 | −10.00 | 114 | |
| INSR | Regulates glucose uptake as well as glycogen, lipid, and protein synthesis [231] | 3EKN | −8.60 | −9.00 | 47 | |
| PTPN9 | Dephosphorylates the insulin receptor, thereby reducing insulin sensitivity [234] | 4GE6 | −7.80 | −8.00 | 246 | |
| RBP4 | Secreted as an adipokine that reduces insulin signaling and promotes gluconeogenesis [235] | 2WR6 | −7.40 | −8.00 | 412 | |
| Regulation of glucose metabolism | AKR1B1 | Catalyzes the reduction of glucose to sorbitol in the polyol pathway, plays a role in diabetic complications [236] | 3G5E | −9.95 | −10.50 | 96 |
| AMY2A | Hydrolyzes alpha-1,4-glycosidic bonds of starch during digestion of starch to glucose [237] | 4GQR | −7.60 | −8.00 | 429 | |
| FBP1 | Catalyzes the second last step in gluconeogenesis [220] | 2JJK | −5.40 | −6.00 | 210 | |
| GCK | Phosphorylates glucose to glucose-6-phosphate for glycolysis or glycogen synthesis [234] | 3IMX | −9.40 | −10.00 | 18 | |
| MGAM | Hydrolyzes 1,4-alpha bonds, the last step in the digestion of starch to glucose [237] | 3L4Y | −6.50 | −7.00 | 592 | |
| PDK2 | Responsible for inactivating the pyruvate dehydrogenase complex that is involved in glucose oxidation [238] | 4MPC | −7.90 | −8.00 | 190 | |
| PYGL | Catalyzes the first step of glycogenolysis by the phosphorolysis of glycogen to glucose-1-phosphate [239] | 3DDS | −8.10 | −8.50 | 113 | |
| Regulation of lipid metabolism | NR5A2 | Regulates the expression of genes involved in bile acid synthesis, cholesterol synthesis, and steroidogenesis [240] | 4DOR | −7.50 | −8.00 | 362 |
| PPARA | Regulates expression of genes involved in lipid metabolism, in particular, the oxidation of fatty acids as well as lipoprotein assembly and lipid transport [241] | 3FEI | −7.60 | −8.00 | 271 | |
| PPARD | Regulates expression of genes involved in fatty acid catabolism [241] | 3PEQ | −9.30 | −10.00 | 60 | |
| PPARG | Regulates expression of genes involved in adipogenesis and lipid metabolism particularly fatty acid transport, lipid droplet formation, triacyglycerol metabolism, as well as lipolysis of triglycerides [241] | 2FVJ | −9.70 | −10.00 | 75 | |
| RXRA | Heterodimerizes with PPARs, thereby initiating gene transcription [241] | 1FM9 | −9.95 | −10.00 | 24 |
Aldose reductase (AKR1B1), dipeptidyl peptidase-4 (DPP4), free fatty acid receptor 1 (FFAR1), fructose-1,6-bisphosphatase (FBP1), glucokinase (GCK), hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1), insulin receptor (INSR), intestinal maltase-glucoamylase (MGAM), liver glycogen phosphorylase (PYGL), liver receptor homolog-1 (NR5A2), pancreatic alpha-amylase (AMY2A), peroxisome proliferator-activated receptor alpha (PPARA), peroxisome proliferator-activated receptor delta (PPARD), peroxisome proliferator-activated receptor gamma (PPARG), protein tyrosine phosphatase, non-receptor type 9 (PTPN9), pyruvate dehydrogenase kinase isoform 2 (PDK2), retinoid X receptor alpha (RXRA), and retinol binding protein 4 (RBP4).