Using PD-L1 full-length structure, enhanced induced fit docking and molecular dynamics simulations for structural insights into inhibition of PD-1/PD-L1 interaction by small-molecule ligands

References

• Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020;20:651–668.
   PubMed Web of Science ®Google Scholar
• Haen SP, Löffler MW, Rammensee H-G, et al. Towards new horizons: characterization, classification and implications of the tumour antigenic repertoire. Nat Rev Clin Oncol. 2020;17:595–610.
   PubMed Web of Science ®Google Scholar
• Zhang H, Chen J. Current status and future directions of cancer immunotherapy. J Cancer. 2018;9:1773–1781.
   PubMed Web of Science ®Google Scholar
• Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–264.
   PubMed Web of Science ®Google Scholar
• Ostrand-Rosenberg S, Horn LA, Haile ST. The programmed death-1 immune-suppressive pathway: barrier to antitumor immunity. J Immunol. 2014;193:3835–3841.
   PubMed Web of Science ®Google Scholar
• Alsaab HO, Sau S, Alzhrani R, et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol. 2017;8:561.
   Web of Science ®Google Scholar
• Wang X, Teng F, Kong L, et al. PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther. 2016;9:5023–5039.
   PubMed Web of Science ®Google Scholar
• Zhan M-M, Hu X-Q, Liu X-X, et al. From monoclonal antibodies to small molecules: the development of inhibitors targeting the PD-1/PD-L1 pathway. Drug Discov Today. 2016;21:1027–1036.
   PubMed Web of Science ®Google Scholar
• Lin X, Lu X, Luo G, et al. Progress in PD-1/PD-L1 pathway inhibitors: from biomacromolecules to small molecules. Eur J Med Chem. 2020;186:111876.
   PubMed Web of Science ®Google Scholar
• Guzik K, Tomala M, Muszak D, et al. Development of the inhibitors that target the PD-1/PD-L1 interaction-A brief look at progress on small molecules, peptides and macrocycles. Molecules. 2019;24:E2071.
   PubMed Web of Science ®Google Scholar
• Chen Y, Liu P, Gao F, et al. A dimeric structure of PD-L1: functional units or evolutionary relics? Protein Cell. 2010;1:153–160.
   PubMed Web of Science ®Google Scholar
• Chaudhri A, Xiao Y, Klee AN, et al. PD-L1 Binds to B7-1 only In Cis on the same cell surface. Cancer Immunol Res. 2018;6:921–929.
   PubMed Web of Science ®Google Scholar
• Sugiura D, Maruhashi T, Okazaki I-M, et al. Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses. Science. 2019;364:558–566.
   PubMed Web of Science ®Google Scholar
• Zinzalla G, Thurston DE. Targeting protein-protein interactions for therapeutic intervention: a challenge for the future. Future Med Chem. 2009;1:65–93.
   PubMed Web of Science ®Google Scholar
• Butte MJ, Peña-Cruz V, Kim M-J, et al. Interaction of human PD-L1 and B7-1. Mol Immunol. 2008;45:3567–3572.
   PubMed Web of Science ®Google Scholar
• Cheng X, Veverka V, Radhakrishnan A, et al. Structure and interactions of the human programmed cell death 1 receptor. J Biol Chem. 2013;288:11771–11785.
   PubMed Web of Science ®Google Scholar
• Lee J-R, Bechstein DJB, Ooi CC, et al. Magneto-nanosensor platform for probing low-affinity protein–protein interactions and identification of a low-affinity PD-L1/PD-L2 interaction. Nat Commun. 2016;7:12220.
   PubMed Web of Science ®Google Scholar
• Lázár-Molnár E, Scandiuzzi L, Basu I, et al. Structure-guided development of a high-affinity human programmed cell death-1: implications for tumor immunotherapy. EBioMedicine. 2017;17:30–44.
   PubMed Web of Science ®Google Scholar
• Magnez R, Thiroux B, Taront S, et al. PD-1/PD-L1 binding studies using microscale thermophoresis. Sci Rep. 2017;7:17623.
   PubMed Web of Science ®Google Scholar
• Lin DY-W, Tanaka Y, Iwasaki M, et al. The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proc Natl Acad Sci U S A. 2008;105:3011–3016.
   PubMed Web of Science ®Google Scholar
• Lázár-Molnár E, Yan Q, Cao E, et al. Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2. Proc Natl Acad Sci U S A. 2008;105:10483–10488.
   PubMed Web of Science ®Google Scholar
• Zak KM, Kitel R, Przetocka S, et al. Structure of the complex of human programmed death 1, PD-1, and its ligand PD-L1. Structure. 2015;23:2341–2348.
   PubMed Web of Science ®Google Scholar
• Zhang F, Wei H, Wang X, et al. Structural basis of a novel PD-L1 nanobody for immune checkpoint blockade. Cell Discov. 2017;3:17004.
   PubMed Web of Science ®Google Scholar
• Zhang Y. I-TASSER server for protein 3D structure prediction. BMC Bioinformatics. 2008;9:40.
   PubMed Web of Science ®Google Scholar
• Xu D, Zhang Y. Improving the physical realism and structural accuracy of protein models by a two-step atomic-level energy minimization. Biophys J. 2011;101:2525–2534.
   PubMed Web of Science ®Google Scholar
• Mandell DJ, Coutsias EA, Kortemme T. Sub-angstrom accuracy in protein loop reconstruction by robotics-inspired conformational sampling. Nat Methods. 2009;6:551–552.
   PubMed Web of Science ®Google Scholar
• Lee GR, Won J, Heo L, et al. Galaxyrefine2: simultaneous refinement of inaccurate local regions and overall protein structure. Nucleic Acids Research. 2019;47:W451–W455.
   PubMed Web of Science ®Google Scholar
• Lomize MA, Lomize AL, Pogozheva ID, et al. OPM: orientations of proteins in membranes database. Bioinformatics. 2006;22:623–625.
   PubMed Web of Science ®Google Scholar
• Lomize AL, Pogozheva ID, Mosberg HI. Anisotropic solvent model of the lipid bilayer. 2. Energetics of insertion of small molecules, peptides, and proteins in membranes. J Chem Inf Model. 2011;51:930–946.
   PubMed Web of Science ®Google Scholar
• Porter KA, Desta I, Kozakov D, et al. What method to use for protein-protein docking? Curr Opin Struct Biol. 2019;55:1–7.
   PubMed Web of Science ®Google Scholar
• Kozakov D, Hall DR, Xia B, et al. The ClusPro web server for protein-protein docking. Nat Protoc. 2017;12:255–278.
   PubMed Web of Science ®Google Scholar
• Tovchigrechko A, Vakser IA. GRAMM-X public web server for protein–protein docking. Nucleic Acids Res. 2006;34:W310–W314.
   PubMed Web of Science ®Google Scholar
• Yan Y, Zhang D, Zhou P, et al. HDOCK: a web server for protein-protein and protein-DNA/RNA docking based on a hybrid strategy. Nucleic Acids Res. 2017;45:W365–W373.
   PubMed Web of Science ®Google Scholar
• Heo L, Lee H, Seok C. Galaxyrefinecomplex: refinement of protein-protein complex model structures driven by interface repacking. Sci Rep. 2016;6:32153.
   PubMed Web of Science ®Google Scholar
• Gray JJ, Moughon S, Wang C, et al. Protein-protein docking with simultaneous optimization of rigid-body displacement and side-chain conformations. J Mol Biol. 2003;331:281–299.
   PubMed Web of Science ®Google Scholar
• Lyskov S, Gray JJ. The RosettaDock server for local protein–protein docking. Nucleic Acids Res. 2008;36:W233–W238.
   PubMed Web of Science ®Google Scholar
• Xue LC, Rodrigues JP, Kastritis PL, et al. PRODIGY: a web server for predicting the binding affinity of protein-protein complexes. Bioinformatics. 2016;32:3676–3678.
   PubMed Web of Science ®Google Scholar
• Bender BJ, Cisneros A, Duran AM, et al. Protocols for molecular modeling with Rosetta3 and RosettaScripts. Biochemistry. 2016;55:4748–4763.
   PubMed Web of Science ®Google Scholar
• Sukhwal A, Sowdhamini R. PPCheck: a webserver for the quantitative analysis of protein-protein interfaces and prediction of residue hotspots. Bioinform Biol Insights. 2015;9:141–151.
   PubMedGoogle Scholar
• Erijman A, Rosenthal E, Shifman JM. How structure defines affinity in protein-protein interactions. PLoS One. 2014;9:e110085.
   PubMed Web of Science ®Google Scholar
• Nilofer C, Sukhwal A, Mohanapriya A, et al. Protein-protein interfaces are vdW dominant with selective H-bonds and (or) electrostatics towards broad functional specificity. Bioinformation. 2017;13:164–173.
   PubMed Web of Science ®Google Scholar
• Friesner RA, Banks JL, Murphy RB, et al. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004;47:1739–1749.
   PubMed Web of Science ®Google Scholar
• Friesner RA, Murphy RB, Repasky MP, et al. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem. 2006;49:6177–6196.
   PubMed Web of Science ®Google Scholar
• Halgren TA, Murphy RB, Friesner RA, et al. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem. 2004;47:1750–1759.
   PubMed Web of Science ®Google Scholar
• Release S. 2017-2: Glide. New York (NY): Schrödinger, LLC; 2018.
   Google Scholar
• Sherman W, Day T, Jacobson MP, et al. Novel procedure for modeling ligand/receptor induced fit effects. J Med Chem. 2006;49:534–553.
   PubMed Web of Science ®Google Scholar
• Sherman W, Beard HS, Farid R. Use of an induced fit receptor structure in virtual screening. Chem Biol Drug Des. 2006;67:83–84.
   PubMed Web of Science ®Google Scholar
• Release S. 2017-2: Induced fit docking protocol; Glide. New York (NY): Schrödinger, LLC; 2018.
   Google Scholar
• Davis IW, Baker D. Rosettaligand docking with full ligand and receptor flexibility. J Mol Biol. 2009;385:381–392.
   PubMed Web of Science ®Google Scholar
• Lemmon G, Meiler J. Rosetta ligand docking with flexible XML protocols. Methods Mol Biol. 2012;819:143–155.
   PubMedGoogle Scholar
• Sastry GM, Adzhigirey M, Day T, et al. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des. 2013;27:221–234.
   PubMed Web of Science ®Google Scholar
• Release S. 2017-2: Protein Preparation Wizard. New York (NY): Schrödinger, LLC; 2016.
   Google Scholar
• Release S. 2017-2: LigPrep. New York (NY): Schrödinger, LLC; 2018.
   Google Scholar
• Jorgensen WL, Maxwell DS, Tirado-Rives J. Development and testing of the OPLS All-atom force field on conformational Energetics and properties of organic liquids. J Am Chem Soc. 1996;118:11225–11236.
   Web of Science ®Google Scholar
• Zak KM, Grudnik P, Guzik K, et al. Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1). Oncotarget. 2016;7:30323–30335.
   PubMed Web of Science ®Google Scholar
• Pronk S, Páll S, Schulz R, et al. GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics. 2013;29:845–854.
   PubMed Web of Science ®Google Scholar
• Huang J, MacKerell AD. CHARMM36 all-atom additive protein force field: validation based on comparison to NMR data. J Comput Chem. 2013;34:2135–2145.
   PubMed Web of Science ®Google Scholar
• Jorgensen WL, Chandrasekhar J, Madura JD, et al. Comparison of simple potential functions for simulating liquid water. J Chem Phys. 1983;79:926–935.
   Web of Science ®Google Scholar
• Bussi G, Donadio D, Parrinello M. Canonical sampling through velocity rescaling. J Chem Phys. 2007;126:014101.
   PubMed Web of Science ®Google Scholar
• Parrinello M, Rahman A. Polymorphic transitions in single crystals: a new molecular dynamics method. J Appl Phys. 1981;52:7182–7190.
   Web of Science ®Google Scholar
• Darden T, York D, Pedersen L. Particle mesh Ewald: an N⋅log(N) method for Ewald sums in large systems. J Chem Phys. 1993;98:10089–10092.
   Web of Science ®Google Scholar
• Essmann U, Perera L, Berkowitz ML, et al. A smooth particle mesh Ewald method. J Chem Phys. 1995;103:8577–8593.
   Web of Science ®Google Scholar
• Vangone A, Schaarschmidt J, Koukos P, et al. Large-scale prediction of binding affinity in protein-small ligand complexes: the PRODIGY-LIG web server. Bioinformatics. 2019;35:1585–1587.
   PubMed Web of Science ®Google Scholar
• Jiménez J, Škalič M, Martínez-Rosell G, et al. KDEEP: protein–ligand absolute binding affinity prediction via 3D-convolutional neural networks. J Chem Inf Model. 2018;58:287–296.
   PubMed Web of Science ®Google Scholar
• Kumari R, Kumar R. Open source drug discovery consortium, et al. g_mmpbsa–a GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model. 2014;54:1951–1962.
   PubMed Web of Science ®Google Scholar
• Salentin S, Schreiber S, Haupt VJ, et al. PLIP: fully automated protein-ligand interaction profiler. Nucleic Acids Res. 2015;43:W443–W447.
   PubMed Web of Science ®Google Scholar
• Scheurer M, Rodenkirch P, Siggel M, et al. Pycontact: rapid, customizable, and visual analysis of noncovalent interactions in MD simulations. Biophys J. 2018;114(3):577–583.
   PubMed Web of Science ®Google Scholar
• Paciotti R, Agamennone M, Coletti C, et al. Characterization of PD-L1 binding sites by a combined FMO/GRID-DRY approach. J Comput Aided Mol Des. 2020;34:897–914.
   PubMed Web of Science ®Google Scholar
• Acúrcio RC, Leonardo-Sousa C, García-Sosa AT, et al. Structural insights and binding analysis for determining the molecular bases for programmed cell death protein ligand-1 inhibition. Medchemcomm. 2019;10(10):1810–1818.
   PubMed Web of Science ®Google Scholar
• Sun X, Liang L, Gu J, et al. Inhibition of programmed cell death protein ligand-1 (PD-L1) by benzyl ether derivatives: analyses of conformational change, molecular recognition and binding free energy. J Biomol Struct Dyn. 2019;37(18):4801–4812.
   PubMed Web of Science ®Google Scholar
• Muszak D, Surmiak E, Plewka J, et al. Terphenyl-based small-molecule inhibitors of programmed cell death-1/programmed death-ligand 1 protein–protein interaction. J Med Chem. 2021;64:11614–11636.
   PubMed Web of Science ®Google Scholar
• Skalniak L, Zak KM, Guzik K, et al. Small-molecule inhibitors of PD-1/PD-L1 immune checkpoint alleviate the PD-L1-induced exhaustion of T-cells. Oncotarget. 2017;8:72167–72181.
   PubMedGoogle Scholar
• Soremekun OS, Olotu FA, Agoni C, et al. Recruiting monomer for dimer formation: resolving the antagonistic mechanisms of novel immune check point inhibitors against programmed death ligand-1 in cancer immunotherapy. Mol Simul. 2019;45:777–789.
   Web of Science ®Google Scholar
• Andrei SA, Sijbesma E, Hann M, et al. Stabilization of protein-protein interactions in drug discovery. Expert Opin Drug Discov. 2017;12:925–940.
   PubMed Web of Science ®Google Scholar
• Tekguc M, Wing JB, Osaki M, et al. Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells. Proc Natl Acad Sci U S A. 2021;118(30):e2023739118.
   PubMed Web of Science ®Google Scholar