Identification of Potential Selective PAK4 Inhibitors Through Shape and Protein Conformation Ensemble Screening and Electrostatic-Surface-Matching Optimization
P21-activated kinase 4 (PAK4) plays a crucial role in the proliferation and metastasis of various cancers. However, developing selective PAK4 inhibitors remains challenging due to the high homology within the PAK family. Therefore, developing highly selective PAK4 inhibitors is critical to overcomin...
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2025-01-01
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| Online Access: | https://www.mdpi.com/1467-3045/47/1/29 |
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| author | Xiaoxuan Zhang Meile Zhang Yihao Li Ping Deng |
| author_facet | Xiaoxuan Zhang Meile Zhang Yihao Li Ping Deng |
| author_sort | Xiaoxuan Zhang |
| collection | DOAJ |
| description | P21-activated kinase 4 (PAK4) plays a crucial role in the proliferation and metastasis of various cancers. However, developing selective PAK4 inhibitors remains challenging due to the high homology within the PAK family. Therefore, developing highly selective PAK4 inhibitors is critical to overcoming the limitations of existing inhibitors. We analyzed the structural differences in the binding pockets of PAK1 and PAK4 by combining cross-docking and molecular dynamics simulations to identify key binding regions and unique structural features of PAK4. We then performed screening using shape and protein conformation ensembles, followed by a re-evaluation of the docking results with deep-learning-driven GNINA to identify the candidate molecule, STOCK7S-56165. Based on this, we applied a fragment-replacement strategy under electrostatic-surface-matching conditions to obtain Compd 26. This optimization significantly improved electrostatic interactions and reduced binding energy, highlighting its potential for selectivity. Our findings provide a novel approach for developing selective PAK4 inhibitors and lay the theoretical foundation for future anticancer drug design. |
| format | Article |
| id | doaj-art-1f44f58d02224f96afcabae22399778d |
| institution | Kabale University |
| issn | 1467-3037 1467-3045 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
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| series | Current Issues in Molecular Biology |
| spelling | doaj-art-1f44f58d02224f96afcabae22399778d2025-01-24T13:27:27ZengMDPI AGCurrent Issues in Molecular Biology1467-30371467-30452025-01-014712910.3390/cimb47010029Identification of Potential Selective PAK4 Inhibitors Through Shape and Protein Conformation Ensemble Screening and Electrostatic-Surface-Matching OptimizationXiaoxuan Zhang0Meile Zhang1Yihao Li2Ping Deng3College of Pharmacy, Chongqing Medical University, Chongqing 400016, ChinaCollege of Pharmacy, Chongqing Medical University, Chongqing 400016, ChinaCollege of Pharmacy, Chongqing Medical University, Chongqing 400016, ChinaCollege of Pharmacy, Chongqing Medical University, Chongqing 400016, ChinaP21-activated kinase 4 (PAK4) plays a crucial role in the proliferation and metastasis of various cancers. However, developing selective PAK4 inhibitors remains challenging due to the high homology within the PAK family. Therefore, developing highly selective PAK4 inhibitors is critical to overcoming the limitations of existing inhibitors. We analyzed the structural differences in the binding pockets of PAK1 and PAK4 by combining cross-docking and molecular dynamics simulations to identify key binding regions and unique structural features of PAK4. We then performed screening using shape and protein conformation ensembles, followed by a re-evaluation of the docking results with deep-learning-driven GNINA to identify the candidate molecule, STOCK7S-56165. Based on this, we applied a fragment-replacement strategy under electrostatic-surface-matching conditions to obtain Compd 26. This optimization significantly improved electrostatic interactions and reduced binding energy, highlighting its potential for selectivity. Our findings provide a novel approach for developing selective PAK4 inhibitors and lay the theoretical foundation for future anticancer drug design.https://www.mdpi.com/1467-3045/47/1/29P21-activated kinasesselective inhibitorsmolecular dockingmolecular dynamicsMM/GBSAelectrostatic complementarity |
| spellingShingle | Xiaoxuan Zhang Meile Zhang Yihao Li Ping Deng Identification of Potential Selective PAK4 Inhibitors Through Shape and Protein Conformation Ensemble Screening and Electrostatic-Surface-Matching Optimization Current Issues in Molecular Biology P21-activated kinases selective inhibitors molecular docking molecular dynamics MM/GBSA electrostatic complementarity |
| title | Identification of Potential Selective PAK4 Inhibitors Through Shape and Protein Conformation Ensemble Screening and Electrostatic-Surface-Matching Optimization |
| title_full | Identification of Potential Selective PAK4 Inhibitors Through Shape and Protein Conformation Ensemble Screening and Electrostatic-Surface-Matching Optimization |
| title_fullStr | Identification of Potential Selective PAK4 Inhibitors Through Shape and Protein Conformation Ensemble Screening and Electrostatic-Surface-Matching Optimization |
| title_full_unstemmed | Identification of Potential Selective PAK4 Inhibitors Through Shape and Protein Conformation Ensemble Screening and Electrostatic-Surface-Matching Optimization |
| title_short | Identification of Potential Selective PAK4 Inhibitors Through Shape and Protein Conformation Ensemble Screening and Electrostatic-Surface-Matching Optimization |
| title_sort | identification of potential selective pak4 inhibitors through shape and protein conformation ensemble screening and electrostatic surface matching optimization |
| topic | P21-activated kinases selective inhibitors molecular docking molecular dynamics MM/GBSA electrostatic complementarity |
| url | https://www.mdpi.com/1467-3045/47/1/29 |
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