Leveraging structural and 2D-QSAR to investigate the role of functional group substitutions, conserved surface residues and desolvation in triggering the small molecule-induced dimerization of hPD-L1
Abstract Small molecules are rising as a new generation of immune checkpoints’ inhibitors, with compounds targeting the human Programmed death-ligand 1 (hPD-L1) protein are pioneering this area of research. Promising examples include the recently disclosed compounds from Bristol-Myers-Squibb (BMS)....
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| Format: | Article |
| Language: | English |
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BMC
2022-06-01
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| Series: | BMC Chemistry |
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| Online Access: | https://doi.org/10.1186/s13065-022-00842-w |
| _version_ | 1818470966544564224 |
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| author | Marawan Ahmed Aravindhan Ganesan Khaled Barakat |
| author_facet | Marawan Ahmed Aravindhan Ganesan Khaled Barakat |
| author_sort | Marawan Ahmed |
| collection | DOAJ |
| description | Abstract Small molecules are rising as a new generation of immune checkpoints’ inhibitors, with compounds targeting the human Programmed death-ligand 1 (hPD-L1) protein are pioneering this area of research. Promising examples include the recently disclosed compounds from Bristol-Myers-Squibb (BMS). These molecules bind specifically to hPD-L1 through a unique mode of action. They induce dimerization between two hPD-L1 monomers through the hPD-1 binding interface in each monomer, thereby inhibiting the PD-1/PD-L1 axis. While the recently reported crystal structures of such small molecules bound to hPD-L1 reveal valuable insights regarding their molecular interactions, there is still limited information about the dynamics driving this unusual complex formation. The current study provides an in-depth computational structural analysis to study the interactions of five small molecule compounds in complex with hPD-L1. By employing a combination of molecular dynamic simulations, binding energy calculations and computational solvent mapping techniques, our analyses quantified the dynamic roles of different hydrophilic and lipophilic residues at the surface of hPD-L1 in mediating these interactions. Furthermore, ligand-based analyses, including Free-Wilson 2D-QSAR was conducted to quantify the impact of R-group substitutions at different sites of the phenoxy-methyl biphenyl core. Our results emphasize the importance of a terminal phenyl ring that must be present in any hPD-L1 small molecule inhibitor. This phenyl moiety overlaps with a very unfavorable hydration site, which can explain the ability of such small molecules to trigger hPD-L1 dimerization. |
| first_indexed | 2024-04-13T21:43:29Z |
| format | Article |
| id | doaj.art-9dd16fb8fa3545478b38c725f03f9bab |
| institution | Directory Open Access Journal |
| issn | 2661-801X |
| language | English |
| last_indexed | 2024-04-13T21:43:29Z |
| publishDate | 2022-06-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Chemistry |
| spelling | doaj.art-9dd16fb8fa3545478b38c725f03f9bab2022-12-22T02:28:39ZengBMCBMC Chemistry2661-801X2022-06-0116112010.1186/s13065-022-00842-wLeveraging structural and 2D-QSAR to investigate the role of functional group substitutions, conserved surface residues and desolvation in triggering the small molecule-induced dimerization of hPD-L1Marawan Ahmed0Aravindhan Ganesan1Khaled Barakat2Faculty of Pharmacy and Pharmaceutical Sciences, University of AlbertaArGan’s Lab, School of Pharmacy, University of WaterlooFaculty of Pharmacy and Pharmaceutical Sciences, University of AlbertaAbstract Small molecules are rising as a new generation of immune checkpoints’ inhibitors, with compounds targeting the human Programmed death-ligand 1 (hPD-L1) protein are pioneering this area of research. Promising examples include the recently disclosed compounds from Bristol-Myers-Squibb (BMS). These molecules bind specifically to hPD-L1 through a unique mode of action. They induce dimerization between two hPD-L1 monomers through the hPD-1 binding interface in each monomer, thereby inhibiting the PD-1/PD-L1 axis. While the recently reported crystal structures of such small molecules bound to hPD-L1 reveal valuable insights regarding their molecular interactions, there is still limited information about the dynamics driving this unusual complex formation. The current study provides an in-depth computational structural analysis to study the interactions of five small molecule compounds in complex with hPD-L1. By employing a combination of molecular dynamic simulations, binding energy calculations and computational solvent mapping techniques, our analyses quantified the dynamic roles of different hydrophilic and lipophilic residues at the surface of hPD-L1 in mediating these interactions. Furthermore, ligand-based analyses, including Free-Wilson 2D-QSAR was conducted to quantify the impact of R-group substitutions at different sites of the phenoxy-methyl biphenyl core. Our results emphasize the importance of a terminal phenyl ring that must be present in any hPD-L1 small molecule inhibitor. This phenyl moiety overlaps with a very unfavorable hydration site, which can explain the ability of such small molecules to trigger hPD-L1 dimerization.https://doi.org/10.1186/s13065-022-00842-wImmune-checkpointsProgrammed cell death ligand 1 (PD-L1)Small molecule drugsComputational solvent mappingFree-WilsonR-group decomposition |
| spellingShingle | Marawan Ahmed Aravindhan Ganesan Khaled Barakat Leveraging structural and 2D-QSAR to investigate the role of functional group substitutions, conserved surface residues and desolvation in triggering the small molecule-induced dimerization of hPD-L1 BMC Chemistry Immune-checkpoints Programmed cell death ligand 1 (PD-L1) Small molecule drugs Computational solvent mapping Free-Wilson R-group decomposition |
| title | Leveraging structural and 2D-QSAR to investigate the role of functional group substitutions, conserved surface residues and desolvation in triggering the small molecule-induced dimerization of hPD-L1 |
| title_full | Leveraging structural and 2D-QSAR to investigate the role of functional group substitutions, conserved surface residues and desolvation in triggering the small molecule-induced dimerization of hPD-L1 |
| title_fullStr | Leveraging structural and 2D-QSAR to investigate the role of functional group substitutions, conserved surface residues and desolvation in triggering the small molecule-induced dimerization of hPD-L1 |
| title_full_unstemmed | Leveraging structural and 2D-QSAR to investigate the role of functional group substitutions, conserved surface residues and desolvation in triggering the small molecule-induced dimerization of hPD-L1 |
| title_short | Leveraging structural and 2D-QSAR to investigate the role of functional group substitutions, conserved surface residues and desolvation in triggering the small molecule-induced dimerization of hPD-L1 |
| title_sort | leveraging structural and 2d qsar to investigate the role of functional group substitutions conserved surface residues and desolvation in triggering the small molecule induced dimerization of hpd l1 |
| topic | Immune-checkpoints Programmed cell death ligand 1 (PD-L1) Small molecule drugs Computational solvent mapping Free-Wilson R-group decomposition |
| url | https://doi.org/10.1186/s13065-022-00842-w |
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