Τhiazolidine-4-One Derivatives with Variable Modes of Inhibitory Action Against DPP4, a Drug Target with Multiple Activities and Established Role in Diabetes Mellitus Type II
<b>Background/Objectives:</b> DPP4 is an enzyme with multiple natural substrates and probable involvement in various mechanisms. It constitutes a drug target for the treatment of diabetes II, although, also related to other disorders. While a number of drugs with competitive inhibitory a...
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2025-01-01
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| author | Dionysia Amanatidou Phaedra Eleftheriou Anthi Petrou Athina Geronikaki Theodoros Lialiaris |
| author_facet | Dionysia Amanatidou Phaedra Eleftheriou Anthi Petrou Athina Geronikaki Theodoros Lialiaris |
| author_sort | Dionysia Amanatidou |
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| description | <b>Background/Objectives:</b> DPP4 is an enzyme with multiple natural substrates and probable involvement in various mechanisms. It constitutes a drug target for the treatment of diabetes II, although, also related to other disorders. While a number of drugs with competitive inhibitory action and covalent binding capacity are available, undesired side effects exist partly attributed to drug kinetics, and research for finding novel, potent, and safer compounds continues. Despite the research, a low number of uncompetitive and non-competitive inhibitors, which could be of worth for pharmaceutical and mechanism studies, was mentioned. <b>Methods:</b> In the present study sixteen 3-(benzo[d]thiazol-2-yl)-2-aryl thiazolidin-4-ones were selected for evaluation, based on structural characteristics and docking analysis and were tested in vitro for DPP4 inhibitory action using H-Gly-Pro-amidomethyl coumarin substrate. Their mode of inhibition was also in vitro explored. <b>Results:</b> Twelve compounds exhibited IC<sub>50</sub> values at the nM range with the best showing IC<sub>50</sub> = 12 ± 0.5 nM, better than sitagliptin. Most compounds exhibited a competitive mode of inhibition. Inhibition modes of uncompetitive, non-competitive, and mixed type were also identified. Docking analysis was in accordance with the in vitro results, with a linear correlation of logIC<sub>50</sub> with a Probability of Binding Factor(PF) derived using docking analysis to a specific target box and to the whole enzyme. According to the docking results, two probable sites of binding for uncompetitive inhibitors were highlighted in the wider area of the active site and in the propeller loop. <b>Conclusions:</b> Potent inhibitors with IC<sub>50</sub> at the nM range and competitive, non-competitive, uncompetitive, and mixed modes of action, one better than sitagliptin, were found. Docking analysis was used to estimate probable sites and ways of binding. However, crystallographic or NMR studies are needed to elucidate the exact way of binding especially for uncompetitive and non-competitive inhibitors. |
| format | Article |
| id | doaj-art-85128b4027be42298c99cf530518e0bc |
| institution | Kabale University |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-01-01 |
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| series | Pharmaceuticals |
| spelling | doaj-art-85128b4027be42298c99cf530518e0bc2025-01-24T13:45:11ZengMDPI AGPharmaceuticals1424-82472025-01-011815210.3390/ph18010052Τhiazolidine-4-One Derivatives with Variable Modes of Inhibitory Action Against DPP4, a Drug Target with Multiple Activities and Established Role in Diabetes Mellitus Type IIDionysia Amanatidou0Phaedra Eleftheriou1Anthi Petrou2Athina Geronikaki3Theodoros Lialiaris4Department of Biomedical Sciences, School of Health, International Hellenic University, 57400 Thessaloniki, GreeceDepartment of Biomedical Sciences, School of Health, International Hellenic University, 57400 Thessaloniki, GreeceDepartment of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, GreeceDepartment of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, GreeceSchool of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece<b>Background/Objectives:</b> DPP4 is an enzyme with multiple natural substrates and probable involvement in various mechanisms. It constitutes a drug target for the treatment of diabetes II, although, also related to other disorders. While a number of drugs with competitive inhibitory action and covalent binding capacity are available, undesired side effects exist partly attributed to drug kinetics, and research for finding novel, potent, and safer compounds continues. Despite the research, a low number of uncompetitive and non-competitive inhibitors, which could be of worth for pharmaceutical and mechanism studies, was mentioned. <b>Methods:</b> In the present study sixteen 3-(benzo[d]thiazol-2-yl)-2-aryl thiazolidin-4-ones were selected for evaluation, based on structural characteristics and docking analysis and were tested in vitro for DPP4 inhibitory action using H-Gly-Pro-amidomethyl coumarin substrate. Their mode of inhibition was also in vitro explored. <b>Results:</b> Twelve compounds exhibited IC<sub>50</sub> values at the nM range with the best showing IC<sub>50</sub> = 12 ± 0.5 nM, better than sitagliptin. Most compounds exhibited a competitive mode of inhibition. Inhibition modes of uncompetitive, non-competitive, and mixed type were also identified. Docking analysis was in accordance with the in vitro results, with a linear correlation of logIC<sub>50</sub> with a Probability of Binding Factor(PF) derived using docking analysis to a specific target box and to the whole enzyme. According to the docking results, two probable sites of binding for uncompetitive inhibitors were highlighted in the wider area of the active site and in the propeller loop. <b>Conclusions:</b> Potent inhibitors with IC<sub>50</sub> at the nM range and competitive, non-competitive, uncompetitive, and mixed modes of action, one better than sitagliptin, were found. Docking analysis was used to estimate probable sites and ways of binding. However, crystallographic or NMR studies are needed to elucidate the exact way of binding especially for uncompetitive and non-competitive inhibitors.https://www.mdpi.com/1424-8247/18/1/52DPP4competitive inhibitorsnon-competitive inhibitorsuncompetitive inhibitorsmixed inhibitionallosteric center |
| spellingShingle | Dionysia Amanatidou Phaedra Eleftheriou Anthi Petrou Athina Geronikaki Theodoros Lialiaris Τhiazolidine-4-One Derivatives with Variable Modes of Inhibitory Action Against DPP4, a Drug Target with Multiple Activities and Established Role in Diabetes Mellitus Type II Pharmaceuticals DPP4 competitive inhibitors non-competitive inhibitors uncompetitive inhibitors mixed inhibition allosteric center |
| title | Τhiazolidine-4-One Derivatives with Variable Modes of Inhibitory Action Against DPP4, a Drug Target with Multiple Activities and Established Role in Diabetes Mellitus Type II |
| title_full | Τhiazolidine-4-One Derivatives with Variable Modes of Inhibitory Action Against DPP4, a Drug Target with Multiple Activities and Established Role in Diabetes Mellitus Type II |
| title_fullStr | Τhiazolidine-4-One Derivatives with Variable Modes of Inhibitory Action Against DPP4, a Drug Target with Multiple Activities and Established Role in Diabetes Mellitus Type II |
| title_full_unstemmed | Τhiazolidine-4-One Derivatives with Variable Modes of Inhibitory Action Against DPP4, a Drug Target with Multiple Activities and Established Role in Diabetes Mellitus Type II |
| title_short | Τhiazolidine-4-One Derivatives with Variable Modes of Inhibitory Action Against DPP4, a Drug Target with Multiple Activities and Established Role in Diabetes Mellitus Type II |
| title_sort | τhiazolidine 4 one derivatives with variable modes of inhibitory action against dpp4 a drug target with multiple activities and established role in diabetes mellitus type ii |
| topic | DPP4 competitive inhibitors non-competitive inhibitors uncompetitive inhibitors mixed inhibition allosteric center |
| url | https://www.mdpi.com/1424-8247/18/1/52 |
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