in silico discovery of potential inhibitors against Dipeptidyl Peptidase-4: A major biological target of Type-2 diabetes mellitus

Abstract

Objectives: Type-2 diabetes mellitus, caused by impaired secretion of insulin, is becoming one of the health hazardous threats to human lives across the world. Its prevalence is rising with time. In this study, 2750 phytochemicals, that are considered to have great ability to eliminate diseases caused by different viruses and bacteria, are obtained from different medicinal plants and discovery of inhibitors through in silico method was performed against Dipeptidyl peptidase-4 (DPP4). Method: The pharmacological assessment and pharmacokinetics of phytochemicals, molecular docking and density functional theory (DFT) analysis helped to explore the inhibitory action of phytochemicals against DPP4. Total forty-nine phytochemicals were screened initially to reduce the number of compounds to be analyzed further based on a threshold of binding affinity ≥-5.5 kcal/mol and were considered for further computational studies to analyze their inhibitory effects for DPP4. For comparison and validation of the results of present study, various previously reported and experimentally validated compounds were docked with the DPP4. For these dockings, binding affinity was predicted and compared with those of phytochemicals to check if these phytochemicals are competent enough to be used as an inhibitor in the treatment of diabetes mellitus in the future. Results: Only four phytochemicals showed binding affinity greater than those of experimentally validated compounds. These included two phytochemicals from Silybum marianum, i.e. Diprenyleriodictyol and Taxifolin and while other two phytochemicals from Santolina insularis and Erythrina Varigatae i.e. Papraline and Osajin respectively. The reactivity levels for these four phytochemicals with the binding site residues of DPP4 were obtained by DFT based analysis, in which ELUMO, EHOMO and band energy gap were computed. Conclusion: Based on these results, it is concluded that these four phytochemicals, after passing through in vitro and in vivo validation, can be utilized as potential DPP4 inhibitors as they have strong properties as compared to those of various experimentally validated inhibitors. with about 300 million cases is to be expected worldwide by 2025 [3]. Both genetic and environmental factors are involved in pathogenicity of type-2 diabetes. It may result in many other disorders like obesity, increased thirst, frequent urination and physical inactivity [4]. There are many symptoms of type-2 diabetes but one of the main symptoms is of raising the blood glucose levels, which is usually caused by impaired In silico discovery of potential inhibitors against Dipeptidyl Peptidase-4: A major biological target of Type-2 diabetes mellitus

The inhibitory effects of toothpaste and mouthwash ingredients on the interaction between the SARS-CoV-2 spike protein and ACE2, and the protease activity of TMPRSS2,in vitro

“…Additionally, gluconic acid and tranexamic acid could weakly bind to human TMPRSS2 at the inhibitor-binding site (Table 4, Fig. 6 B) (Zhong et al, 2019; Andleeb et al, 2020). These results supported the results of the in vitro assay.…”

The Effectiveness of Antidiabetic Drugs in Treating Dementia: A Peek into Pharmacological and Pharmacokinetic Properties

“…DPP-4 inhibitors prevent the degradation of GLP-1 by DPP-4 and induce insulin secretion. DPP-4 inhibitors, except for teneligliptin and trelagliptin, do not penetrate the BBB, as predicted by ADMET analysis [ 77 ]. Teneligliptin and trelagliptin have been experimentally validated to penetrate the BBB [ 77 ].…”

“…DPP-4 inhibitors, except for teneligliptin and trelagliptin, do not penetrate the BBB, as predicted by ADMET analysis [ 77 ]. Teneligliptin and trelagliptin have been experimentally validated to penetrate the BBB [ 77 ]. [ 14 C]-radiolabeled linagliptin was not detected in the brain after a single intravenous administration in rats [ 40 ].…”

“…DPP-4 causes a rapid degradation of endogenous GLP-1 secreted from the intestine [ 69 ]; thus, if DPP-4 is inhibited by a DPP-4 inhibitor, GLP-1 secreted from the intestine can reach the brain. However, DPP-4 is ubiquitous in the brain [ 29 ], and thus, GLP-1 can be rapidly degraded after being translocated into the brain because almost all DPP-4 inhibitors cannot permeate the BBB [ 40 , 77 ]. Some observational studies have shown the beneficial effects of DPP-4 inhibitors on the risk of dementia.…”

The inhibitory effects of toothpaste and mouthwash ingredients on the interaction between the SARS-CoV-2 spike protein and ACE2, and the protease activity of TMPRSS2 in vitro

“…The obtained AutoDock Vina scores and docking modes indicated that N-lauroyl-N-methyltaurine, N-lauroylsarcosine, gluconic acid, dodecyl sulfate, and (E)-tetradec-1-ene-1-sulfonic acid could weakly bind to human ACE2 at the inhibitor-binding site (Table 3, Fig 6A) [22,23]. Additionally, gluconic acid and tranexamic acid could weakly bind to human TMPRSS2 at the inhibitor-binding site (Table 4, Fig 6B) [23,24]. The docking simulations using the refined human TMPRSS2 crystal structure (PDB ID: 7MEQ) gave a similar AutoDock Vina score and docking mode for these test ingredients (S2 Fig and S2 Table).…”