Identification of levomenthol derivatives as potential dipeptidyl peptidase-4 inhibitors: a comparative study with gliptins.

Dipeptidyl peptidase-4 (DPP4) inhibitors are a potent therapeutic treatment for type 2 diabetes mellitus (T2DM). There is a family of compounds used as DPP4 inhibitors (DPP4Is) called gliptins. They bind tightly to DPP4 to form an inactive protein-ligand complex. However, there remains a need to identify novel DPP4Is that are more efficacious and safer due to the increasing prevalence of T2DM and the undesirable side effects of gliptins. To identify potential DPP4Is, we screened over 1800 novel compounds in a comparative study with gliptins. We performed dual-factor molecular docking to assess the binding affinity of the compounds to DPP4 and found four compounds with a higher binding affinity to DPP4 than currently used gliptins. The newly identified compounds interacted with the dyad glutamate (GLU205 and GLU206) and tyrosine (TYR662 and TYR666) residues in DPP4's active site. We performed molecular dynamics simulations to determine the stability of the protein-ligand complexes formed by the compounds and DPP4. Furthermore, we examined the toxicity and pharmacological profile of the compounds. The compounds are drug-like, easy to synthesize, and relatively less toxic than gliptins. Collectively, our results suggest that the novel compounds are potential DPP4Is and should be considered for further studies to develop novel antidiabetics.Communicated by Ramaswamy H. Sarma.

Potential Inhibitory Biomolecular Interactions of Natural Compounds With Different Molecular Targets of Diabetes.

Type II diabetes is an endemic disease and is responsible for approximately 90% to 95% of diabetes cases. The pathophysiological distortions are majorly ß-cell dysfunction, insulin resistance, and long-term inflammation, which all progressively unsettle the control of blood glucose levels and trigger microvascular and macrovascular complications. The diverse pathological disruptions which patients with type II diabetes mellitus exhibit precipitate the opinion that different antidiabetic agents, administered in combination, might be required to curb this menace and maintain normal blood glucose. To this end, natural compounds were screened to identify small molecular weight compounds with inhibitory effects on protein tyrosine phosphatase 1B (PTP1B), dipeptidyl-peptidase-4 (DPP-4), and α-amylase. From the result, the top 5 anthocyanins with the highest binding affinity are reported herein. Further ADMET profiling showed moderate pharmacokinetic profiles for these compounds as well as insignificant toxicity. Cyanidin 3-(p-coumaroyl)-diglucoside-5-glucoside (-15.272 kcal/mol), cyanidin 3-O-(6"-malonyl-3"-glucosyl-glucoside) (-9.691 kcal/mol), and delphinidin 3,5-O-diglucoside (-12.36 kcal/mol) had the highest binding affinities to PTP1B, DPP-4, and α-amylase, respectively, and can be used in combination to control glucose fluctuations. However, validations must be carried out through further in vitro and in vivo tests.

Molecular dynamics simulation and pharmacokinetics studies of ombuin and quercetin against human pancreatic α-amylase.

Diabetes mellitus (DM) is a group of metabolic disorders characterised by chronic hyperglycaemia. DM is currently one of the top ten causes of death in humans. Chronic hyperglycaemia in DM leads to long-term damage and failure of different organs in the body. Type 2 DM (T2D) is the most common DM form, characterised by peripheral insulin resistance, relative insulin deficiency, impaired hepatic glucose production regulation and pancreatic ß cell dysfunction. The human pancreatic α-amylase (HPA) inhibitor is currently one of the most effective methods developed to inhibit hyperglycaemia in T2D patients. However, the current standard drug available, acarbose, has been associated with severe side effects following prolonged use in patients. Therefore, an alternative drug capable of effectively inhibiting HPA with minimal side effects is required. Based on our previous study, we further explored the therapeutic potential of quercetin and ombuin via molecular dynamics (MD) simulation. The Desmond Simulation Package was used to run 100-ns MD simulations to examine the steady nature and conformational stability of the ligand-HPA complexes. Post-simulation molecular mechanics-generalised born surface area (MM-GBSA) analysis of HPA's binding free energy with quercetin and ombuin was explored. The lead compounds' drug-likeness, absorption, distribution, metabolism and elimination properties were also studied using the SwissADME tool. These results indicate that quercetin and ombuin have great potential as anti-DM drugs with more favourable properties than acarbose.Communicated by Ramaswamy H. Sarma.