Molecular modelling as a tool for designing dipeptidylpeptidase-4 inhibitors

2021 ◽  
Vol 10 (1) ◽  
pp. 26-39
Author(s):  
Ahmed Mehanna ◽  
Moataz Hendawy
Keyword(s):  
Docking Studies ◽  
Binding Modes ◽  
Dipeptidyl Peptidase 4 ◽  
Effective Implementation ◽  
Ic50 Values ◽  
Modelling Studies ◽  
Dipeptidylpeptidase 4 ◽  
Key Residues ◽  
New Compounds

Dipeptidyl peptidase-4 (DPP-4) is a relatively new target for the treatment of type-2 diabetes mellitus (T2DM). Most of the inhibitors designed to date have not relied on modelling studies to guide their lead optimization efforts. In our previous work, we designed compounds that retain the (R)-3-amino-4-(2,4,5-trifluorophenyl)butanamido S1-pocket binding moiety of sitagliptin, but have S2-pocket binding moieties that are more hydrophobic than the triazolopiperazine. In an effort to understand how Vina docking algorithm can be integrated in discovering new inhibitors of DPP-4; we designed, synthesized and evaluated new compounds that vary in the hydrophobic properties of the S2-pocket binding groups. Our results indicate that the minimum binding energy predicted from the docking studies was not reliable in designing more active candidates. However, visualizing the binding modes of each compound and modifying it to target neighboring key residues in the active site is a more effective implementation of the docking in the design of new compounds. Compounds in this study displayed IC50 values ranging from 0.37 µM to 11 µM.

Synthesis, investigation of biological effects and in silico studies of new benzimidazole derivatives as aromatase inhibitors

2020 ◽  
Vol 75 (9-10) ◽  
pp. 353-362
Author(s):  
Begüm Nurpelin Sağlık ◽  
Ahmet Mücahit Şen ◽  
Asaf Evrim Evren ◽  
Ulviye Acar Çevik ◽  
Derya Osmaniye ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
In Silico ◽  
Biological Effects ◽  
Docking Studies ◽  
Benzimidazole Derivatives ◽  
Binding Modes ◽  
Reference Drug ◽  
In Silico Studies ◽  
New Compounds ◽  
Mcf 7

AbstractInhibition of aromatase enzymes is very important in the prevention of estrogen-related diseases and the regulation of estrogen levels. Aromatase enzyme is involved in the final stage of the biosynthesis of estrogen, in the conversion of androgens to estrogen. The development of new compounds for the inhibition of aromatase enzymes is an important area for medicinal chemists in this respect. In the present study, new benzimidazole derivatives have been designed and synthesized which have reported anticancer activity in the literature. Their anticancer activity was evaluated against human A549 and MCF-7 cell lines by MTT assay. In the series, concerning MCF-7 cell line, the most potent compounds were the 4-benzylpiperidine derivatives 2c, 2g, and 2k with IC50 values of 0.032 ± 0.001, 0.024 ± 0.001, and 0.035 ± 0.001 µM, respectively, compared to the reference drug cisplatin (IC50 = 0.021 ± 0.001 µM). Then, these compounds were subject to further in silico aromatase enzyme inhibition assays to determine the possible binding modes and interactions underlying their activity. Thanks to molecular docking studies, the effectiveness of these compounds against aromatase enzyme could be simulated. Consequently, it has been found that these compounds can be settled very properly to the active site of the aromatase enzyme.

scholarly journals Molecular Docking Studies of Phenolic Compounds from Syzygium cumini with Multiple Targets of Type 2 Diabetes

2018 ◽  
Vol 6 (2) ◽  
pp. 125-133
Author(s):  
Ajmer Singh Grewal ◽  
Neelam Sharma ◽  
Sukhbir Singh ◽  
Sandeep Arora
Keyword(s):  
Type 2 Diabetes ◽  
Phenolic Compounds ◽  
Side Effects ◽  
In Silico ◽  
Glycogen Synthase ◽  
Dipeptidyl Peptidase ◽  
Docking Studies ◽  
Multiple Targets ◽  
Dipeptidyl Peptidase 4

Treatment of type 2 diabetes without any side effects is still a challenge to the medical system. This leads to increasing demand for natural products with antidiabetic activity with fewer side effects. Syzygium cumini is a traditional herbal medicinal plant and is reported to possess a variety of pharmacological actions. It contains various types of chemical constituents including terpenoids, tannins, anthocyanins, flavonoids and other phenolic compounds. Some flavonoids and other phenolic compounds from S. cumini were reported in literature to have type 2 antidiabetic potential. The main objective of the current investigation was in silico screening of some phenolic compounds from S. cumini against multiple targets associated with type 2 diabetes to explore the mechanism of antidiabetic action and prediction of binding mode using molecular docking studies. In silico docking studies were performed for the selected molecules in the binding site of multiple targets associated with type 2 diabetes (α-glucosidas , dipeptidyl peptidase 4, glycogen synthase kinase 3, glucokinase and glucagon receptor). Amongst the compounds tested in silico, rutin showed appreciable binding with multiple targets of type 2 diabetes including α-glucosidase, dipeptidyl peptidase 4, glycogen synthase kinase 3, and glucagon receptor. Catechin was found to inhibit both α-glucosidase, and dipeptidyl peptidase 4. This information can be utilized for the design and development of potent multi-functional candidate drugs with minimal side effects for type 2 diabetes therapeuticsa.

Tacrine-coumarin and Tacrine-7-chloroquinoline Hybrids with Thiourea Linkers: Cholinesterase Inhibition Properties, Kinetic Study, Molecular Docking and Permeability Assay for Blood-brain Barrier

2018 ◽  
Vol 15 (12) ◽  
pp. 1096-1105 ◽  
Author(s):  
Slavka Hamulakova ◽  
Ladislav Janovec ◽  
Ondrej Soukup ◽  
Daniel Jun ◽  
Jana Janockova ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Mixed Type ◽  
Acetylcholinesterase Inhibitors ◽  
Docking Studies ◽  
Brain Barrier ◽  
Ache Inhibitor ◽  
Cholinesterase Inhibition ◽  
Binding Modes ◽  
Blood Brain ◽  
Ic50 Values

Background: The design of new heterodimeric dual binding site acetylcholinesterase inhibitors constitutes the main goal-directed to the development of new anticholinesterase agents with the expanded pharmacological profile. Multi-target compounds are usually designed by combining in a hybrid molecule with two or more pharmacophoric moieties that are known to enable interaction with the selected molecular targets. Methods: All compounds were tested for their inhibitory activity on human AChE/BChE. The Ellman´s method was used to determine inhibition kinetics and IC50 values. In order to predict passive bloodbrain penetration of novel compounds, modification of the parallel artificial membrane permeation assay has been used. Docking studies were performed in order to predict the binding modes of new hybrids with hAChE/ hBChE respectively. Results: In this study, we described the design, synthesis, and evaluation of series tacrine-coumarin and tacrine-quinoline compounds which were found to show potential inhibition of ChEs and penetration of the blood-brain barrier. Conclusion: Tacrine-quinoline hybrids 7a exhibited the highest activity towards hBChE (IC50 = 0.97 µmol) and 7d towards hAChE (IC50 = 0.32 µmol). Kinetic and molecular modelling studies revealed that 7d was a mixed-type AChE inhibitor (Ki = 1.69 µmol) and 7a was a mixed-type BChE inhibitor (Ki = 1.09 µmol). Moreover, hybrid 5d and 7c could penetrate the CNS.

scholarly journals 6-Amino-4-Aryl-3-Carbamoyl-5-Cyano-1,4-Dihydropyridine-2-Thiolates: Synthesis, Reactions and Docking Studies

2020 ◽  
Vol 3 (1) ◽  
pp. 13
Author(s):  
Nawras T. Jassim ◽  
Victor V. Dotsenko ◽  
Nicolai A. Aksenov
Keyword(s):  
Calcium Channel ◽  
Interaction Mechanism ◽  
Docking Studies ◽  
Channel Blockers ◽  
Binding Modes ◽  
Reference Drug ◽  
Mild Conditions ◽  
Channel Proteins ◽  
New Compounds ◽  
Synthesis Reactions

New triethylammonium 6-amino-4-aryl-3-carbamoyl-5-cyano-1,4-dihydropyridine-2-thiolates were prepared in good yields by the ternary condensation of malononitrile, aldehydes and monothiomalonamide in the presence of Et3N. The thiolates underwent S-alkylation under mild conditions to produce new 1,4-dihydronicotinamides. Molecular docking studies were carried out in order to explore the interaction mechanism and to investigate suitable binding modes of the new compounds on the calcium channel proteins. Some of the compounds in the in silico experiments were found to be more potent as calcium channel blockers than the reference drug, Nifedipine.

scholarly journals Bio-Potency and Molecular Docking Studies of Isolated Compounds from Grewia optiva J.R. Drumm. ex Burret

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 2019
Author(s):  
Wasim Ul Bari ◽  
Najeeb Ur Rehman ◽  
Ajmal Khan ◽  
Sobia Ahsan Halim ◽  
Ye Yuan ◽  
...  
Keyword(s):  
Radical Scavenging ◽  
Docking Studies ◽  
Drug Candidate ◽  
In Silico Docking ◽  
Ic50 Values ◽  
Grewia Optiva ◽  
New Compounds ◽  
First Time

In the study, two novel compounds along with two new compounds were isolated from Grewia optiva. The novel compounds have never been reported in any plant source, whereas the new compounds are reported for the first time from the studied plant. The four compounds were characterized as: 5,5,7,7,11,13-hexamethyl-2-(5-methylhexyl)icosahydro-1H-cyclopenta[a]chrysen-9-ol (IX), docosanoic acid (X), methanetriol mano formate (XI) and 2,2’-(1,4-phenylene)bis(3-methylbutanoic acid (XII). The anticholinesterase, antidiabetic, and antioxidant potentials of these compounds were determined using standard protocols. All the isolated compounds exhibited a moderate-to-good degree of activity against acetylcholinesterases (AChE) and butyrylcholinesterase (BChE). However, compound XII was particularly effective with IC50 of 55 μg/mL (against AChE) and 60 μg/mL (against BChE), and this inhibitory activity is supported by in silico docking studies. The same compound was also effective against DPPH (2, 2-diphenyl-1-picrylhydrazyl) and ABTS (2, 2′-azinobis-3-ethylbenzothiazoline-6-sulfonic acid) radicals with IC50 values of 60 and 62 μg/mL, respectively. The compound also significantly inhibited the activities of α-amylase and α-glucosidase in vitro. The IC50 values for inhibition of the two enzymes were recorded as 90 and 92 μg/mL, respectively. The in vitro potentials of compound XII to treat Alzheimer’s disease (in terms of AchE and BChE inhibition), diabetes (in terms of α-amylase and α-glucosidase inhibition), and oxidative stress (in terms of free radical scavenging) suggest further in vivo investigations of the compound for assessing its efficacy, safety profile, and other parameters to proclaim the compound as a potential drug candidate.

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