Identification of Activated Cdc42-Associated Kinase Inhibitors as Potential Anticancer Agents Using Pharmacoinformatic Approaches
Background: Activated Cdc42-associated kinase (ACK1) is essential for numerous cellular functions, such as growth, proliferation, and migration. ACK1 signaling occurs through multiple receptor tyrosine kinases; therefore, its inhibition can provide effective antiproliferative effects against multipl...
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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/2/217 |
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| author | Vikas Kumar Raj Kumar Shraddha Parate Danishuddin Gihwan Lee Moonhyuk Kwon Seong-Hee Jeong Hyeon-Su Ro Keun Woo Lee Seon-Won Kim |
| author_facet | Vikas Kumar Raj Kumar Shraddha Parate Danishuddin Gihwan Lee Moonhyuk Kwon Seong-Hee Jeong Hyeon-Su Ro Keun Woo Lee Seon-Won Kim |
| author_sort | Vikas Kumar |
| collection | DOAJ |
| description | Background: Activated Cdc42-associated kinase (ACK1) is essential for numerous cellular functions, such as growth, proliferation, and migration. ACK1 signaling occurs through multiple receptor tyrosine kinases; therefore, its inhibition can provide effective antiproliferative effects against multiple human cancers. A number of ACK1-specific inhibitors were designed and discovered in the previous decade, but none have reached the clinic. Potent and selective ACK1 inhibitors are urgently needed. Methods: In the present investigation, the pharmacophore model (PM) was rationally built utilizing two distinct inhibitors coupled with ACK1 crystal structures. The generated PM was utilized to screen the drug-like database generated from the four chemical databases. The binding mode of pharmacophore-mapped compounds was predicted using a molecular docking (MD) study. The selected hit-protein complexes from MD were studied under all-atom molecular dynamics simulations (MDS) for 500 ns. The obtained trajectories were ranked using binding free energy calculations (ΔG kJ/mol) and Gibb’s free energy landscape. Results: Our results indicate that the three hit compounds displayed higher binding affinity toward ACK1 when compared with the known multi-kinase inhibitor dasatinib. The inter-molecular interactions of Hit1 and Hit3 reveal that compounds form desirable hydrogen bond interactions with gatekeeper T205, hinge region A208, and DFG motif D270. As a result, we anticipate that the proposed scaffolds might help in the design of promising selective ACK1 inhibitors. |
| first_indexed | 2024-03-11T09:06:26Z |
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| id | doaj.art-e970ecfa97494357aa8a944b1a8e960c |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-11T09:06:26Z |
| publishDate | 2023-01-01 |
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| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-e970ecfa97494357aa8a944b1a8e960c2023-11-16T19:22:00ZengMDPI AGBiomolecules2218-273X2023-01-0113221710.3390/biom13020217Identification of Activated Cdc42-Associated Kinase Inhibitors as Potential Anticancer Agents Using Pharmacoinformatic ApproachesVikas Kumar0Raj Kumar1Shraddha Parate2Danishuddin3Gihwan Lee4Moonhyuk Kwon5Seong-Hee Jeong6Hyeon-Su Ro7Keun Woo Lee8Seon-Won Kim9Department of Bio & Medical Big Data (BK4 Program), Division of Life Science, Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Republic of KoreaDepartment of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan 173 234, Himachal Pradesh, IndiaDivision of Applied Life Science, Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Republic of KoreaDepartment of Bio & Medical Big Data (BK4 Program), Division of Life Science, Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Republic of KoreaANGEL i-Drug Design (AiDD), Jinju 52828, Republic of KoreaDivision of Applied Life Science (BK21 Four), ABC-RLRC, PMBBRC, Gyeongsang National University, Jinju 52828, Republic of KoreaDivision of Applied Life Science (BK21 Four), ABC-RLRC, PMBBRC, Gyeongsang National University, Jinju 52828, Republic of KoreaDepartment of Bio & Medical Big Data (BK4 Program), Division of Life Science, Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Republic of KoreaDepartment of Bio & Medical Big Data (BK4 Program), Division of Life Science, Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Republic of KoreaDivision of Applied Life Science (BK21 Four), ABC-RLRC, PMBBRC, Gyeongsang National University, Jinju 52828, Republic of KoreaBackground: Activated Cdc42-associated kinase (ACK1) is essential for numerous cellular functions, such as growth, proliferation, and migration. ACK1 signaling occurs through multiple receptor tyrosine kinases; therefore, its inhibition can provide effective antiproliferative effects against multiple human cancers. A number of ACK1-specific inhibitors were designed and discovered in the previous decade, but none have reached the clinic. Potent and selective ACK1 inhibitors are urgently needed. Methods: In the present investigation, the pharmacophore model (PM) was rationally built utilizing two distinct inhibitors coupled with ACK1 crystal structures. The generated PM was utilized to screen the drug-like database generated from the four chemical databases. The binding mode of pharmacophore-mapped compounds was predicted using a molecular docking (MD) study. The selected hit-protein complexes from MD were studied under all-atom molecular dynamics simulations (MDS) for 500 ns. The obtained trajectories were ranked using binding free energy calculations (ΔG kJ/mol) and Gibb’s free energy landscape. Results: Our results indicate that the three hit compounds displayed higher binding affinity toward ACK1 when compared with the known multi-kinase inhibitor dasatinib. The inter-molecular interactions of Hit1 and Hit3 reveal that compounds form desirable hydrogen bond interactions with gatekeeper T205, hinge region A208, and DFG motif D270. As a result, we anticipate that the proposed scaffolds might help in the design of promising selective ACK1 inhibitors.https://www.mdpi.com/2218-273X/13/2/217ACK1pharmacophore modelingdockingmolecular dynamics simulationscancerinhibitor |
| spellingShingle | Vikas Kumar Raj Kumar Shraddha Parate Danishuddin Gihwan Lee Moonhyuk Kwon Seong-Hee Jeong Hyeon-Su Ro Keun Woo Lee Seon-Won Kim Identification of Activated Cdc42-Associated Kinase Inhibitors as Potential Anticancer Agents Using Pharmacoinformatic Approaches Biomolecules ACK1 pharmacophore modeling docking molecular dynamics simulations cancer inhibitor |
| title | Identification of Activated Cdc42-Associated Kinase Inhibitors as Potential Anticancer Agents Using Pharmacoinformatic Approaches |
| title_full | Identification of Activated Cdc42-Associated Kinase Inhibitors as Potential Anticancer Agents Using Pharmacoinformatic Approaches |
| title_fullStr | Identification of Activated Cdc42-Associated Kinase Inhibitors as Potential Anticancer Agents Using Pharmacoinformatic Approaches |
| title_full_unstemmed | Identification of Activated Cdc42-Associated Kinase Inhibitors as Potential Anticancer Agents Using Pharmacoinformatic Approaches |
| title_short | Identification of Activated Cdc42-Associated Kinase Inhibitors as Potential Anticancer Agents Using Pharmacoinformatic Approaches |
| title_sort | identification of activated cdc42 associated kinase inhibitors as potential anticancer agents using pharmacoinformatic approaches |
| topic | ACK1 pharmacophore modeling docking molecular dynamics simulations cancer inhibitor |
| url | https://www.mdpi.com/2218-273X/13/2/217 |
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