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WIREs Comput Mol Sci
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Computer‐aided drug design in new druggable targets for the next generation of immune‐oncology therapies

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Immune modulatory pathways have emerged as innovative and successful targets in cancer immunotherapy. Current therapeutics include monoclonal antibodies, which have shown impressive clinical results in the treatment of several types of tumors. However, the failure to show response in the majority of patients and the induction of severe immune‐related adverse effects are among the major drawbacks. Latest efforts to achieve new approaches to target additional pathways and/or protein responsible for immune evasion toward the development of immune modulatory small molecules have been devised. The potential of innovative computational‐aided drug design tools to accelerate the identification and design of new optimized and validated immune small molecules modulators will play a key role in the next generation of cancer immunotherapy drug discovery. Nevertheless, the lack of structural information regarding the immune modulatory pathways and other components within tumor microenvironment has hampered the rational design of those small‐molecule modulators, by preventing the use of such methodologies. Herein we provide an overview on structural elucidation on known regulators of immune modulatory pathways (adenosine A2A receptor [A2AR], stimulator of interferon genes [STING], indoleaine 2,3‐dioxygenase 1 [IDO1], and 4‐1BB) within cancer microenvironment. This knowledge on immune modulatory molecular targets is essential to advance the understanding of their binding mode and guide the design of novel effective targeted anticancer medicines.

This article is categorized under:

  • Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods
  • Structure and Mechanism > Molecular Structures
  • Software > Molecular Modeling
STING dimer. (a) Cartoon representation of STING dimer. One protomer is colored in orange ribbon. The other protomer is colored in teal. The interacting α1 and α3 are labeled for both protomers. Detailed interaction at the dimer interface. Interfacial residues are shown as sticks. (b) Surface representation of the STING dimer in a side view, showing the deep crevice across the dimer interface, and the electrostatic surface of the STING dimer shown in a top view. One molecule is colored in orange and the other in teal, as in (a)
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A2AR ligands identified by in silico approaches
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A2AR inverse‐agonists and agonists
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A2AR: Inverse agonist complex A1 and A2A receptors. (a) Binding interactions between the A2AR and compound 8. The side chains of residues are shown in green sticks. Dashed lines depict hydrogen bond interactions. The π−π stacking interaction of the aminotriazole ring with the Phe168 is depicted with dashed green line. The hydrogen bonding interactions with the side chains of Asn253 and Glu169 are depicted with dashed yellow lines. (b) Binding site of A2A with theophylline. The side chains of residues are shown in green sticks. The hydrogen bonding interactions with the side chains of Asn253 and His278 are depicted with dashed yellow lines. (c) Superposition of backbone ribbons of the A1 complexed with PSB36, in blue, and the A2AR structure in complex with ZM241385, in gray. (d) Comparison of binding modes of PSB36 in A1 and A2AR. Superposition of the structures of the A1R (blue ribbon) with PSB36 (salmon), and the A2AR (gray ribbon) with PSB36 (gray)
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DMXAA:STING complex and STING activation. (a) The crystal structure of two molecules of DMXAA bound to murine STING. (b) Intermolecular contacts in the complex of DMXAA bound to murine STING. The two bound DMXAA molecules are shown in light green color, with individual murine STING subunits in the symmetrical dimer shown in dark orange and teal. The intermolecular contacts to the polar and nonpolar edges of the DMXAA by the murine STING subunits are shown in two alternate views. (c) Superposition of the DMXAA‐bound structure of murine STING (light orange and light blue) and the DMXAA‐bound structure of human STING (dark orange and teal). (d) The structural basis of IRF‐3 recruitment by STING. Residues of the pLxIS motif are represented by orange sticks. Close‐up view of the STING/IRF‐3 complex. IRF‐3 is shown by light blue ribbons
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A2AR‐inverse agonists bound structures. (a) Comparison of ligand positions in the structure‐binding site cavity. The structure of A2AR is depicted as a gray surface. The ligands are represented as sticks, ZM241385 (dark blue), XAC (green), and caffeine (orange), oxygen atoms are red, and nitrogen atoms blue. (b) and (c) 1,2,4‐triazine adenosine A2A antagonists. Compounds 26 and 27 are illustrated bound to the pocket of the receptor and the residues lining the pocket that interact with the ligands are labeled. Yellow dashed lines highlight the key hydrogen bonding to Asn253 of the scaffold. TM helices and visible extracellular regions are depicted in gray cartoon. Ligands are represented as stick models; residues involved in ligand binding are labeled and represented as green sticks
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A2AR‐agonist bound structures. (a) Ligand UK‐432097 and its binding cavity. Overall view of the ligand‐binding cavity. The transmembrane part of A2AR is shown as ribbon and colored gray. Ligand UK‐432097 is shown as yellow sticks. Molecular interactions within the ligand‐binding cavity for UK‐432097. Interacting residues are shown as sticks. Hydrogen bonds between A2AR and ligand are shown as yellow dashed lines. (b1) Superposition of A2AR bound to the inverse agonist ZM241385 (orange sticks) and the agonist UK‐432097 (yellow sticks). (b2) A2AR bound to NECA (salmon) and adenosine (pink). (c) Ligand‐binding mode of the selective agonist CGS21680. Structure of the extracellular portion of A2AR bound to the selective agonist CGS21680. Elements of the structure are depicted as follows: A2AR illustration (gray ribbons); specific amino acid side chains, sticks; CGS21680, dark blue sticks; hydrogen bonds, yellow dashed line; π−π stacking interaction green dashed line. (d) Comparison of the ligand‐binding site of the human A2AR bound to various ligands (PDB IDs are shown in parentheses): NECA (2YDV), CGS21680, UK432097 (3QAK), and adenosine (2YDO)
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A2AR structure. (a) Structure of A2AR in rainbow coloration (yellow to blue). The visible extracellular and intracellular loops are labeled. The disordered portion of ECL2 is not completed. (b) Structure of A2A‐ZM241385 in rainbow coloration (yellow to blue) from the N terminus to the C terminus, ZM241385 is represented as a stick model (yellow), (c) close‐up view of A2AR pocket of ZM241385 (yellow) and details of the hydrogen bonds network (yellow dash line) together with π–π stacking (green dash line). (d) Distribution of ordered waters in A2AR. Buried water molecules (red spheres) in the A2AR‐ZM241385 structure form an almost‐continuous water channel containing three major water clusters. Close‐up view of the central cluster, which includes waters and a sodium ion (cyan sphere)
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CADD in drug discovery
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4‐1BBL structures (PDBID: 2X29). (a) Ribbon representation of 4‐1BBL (green). The structure shows a two‐layered jellyroll β‐sandwich topology similar to the canonical structure of the other TNF family members. The inner and outer sheets of the jelly‐roll β‐sandwich are composed of A'HCF and ABGDE, respectively. (b) The residues involved in the hydrophobic interactions are: Gln89, Val140, Leu203, His205, Val240, Thr241, Pro242, and Pro245 in one protomer (green) and Gln94, Phe92, Leu115, Tyr142, Phe144, Phe197, and Phe199 in the adjacent protomer (green). (c) Ribbon representation of 4‐1BBL trimer. 4‐1BBL forms a three‐fold symmetric assembly resembling a three‐bladed propeller. The interactions between 4‐1BBL subunits in the trimer are primarily mediated by hydrophobic interactions between the C‐terminal tail of one subunit and the A'B loop and the A’, C, and F strands of the adjacent subunit
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IDO1 inhibitors. Epacadostat 40 started clinical testing in 2014 and is currently in phase II of clinical trials being the most advanced IDO1 inhibitor. Indoximod 38 started clinical testing in 2008 and is currently in phase I of clinical trials. In 2014, NLG919 39 started clinical testing and it is in phase I of clinical trials. Also 41 as initiated clinical trials. The clinical evaluation that is occurring use the molecules as only therapeutic or in combination with others
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IDO1/substrate, IDO1/IDE and IDO1/epacadostat complexes. (a) Crystal structure of the IDO1‐Trp complex. Binding mode of Trp (yellow sticks). Trp binds in the distal heme (green) pocket A (yellow) and occupy the pocket B (salmon). The Trp interacts with the protein and heme, via various hydrophobic and polar interactions as represented by yellow dashes. (b) New small molecule binding site in IDO1. Crystal structure of the IDO1‐Trp complex in a mixed ligand state, where active site and the new site are occupied by Trp and IDE (cyan), respectively. The hydrophobic residues forming the base of the binding pocket are shown as magenta sticks, while pockets A and B are shown in yellow and salmon sticks. IED‐IDO1 protein interactions are represented in yellow dashes. (c) Binding mode of epacadostat (33) to IDO1. Protein surface is represented in blue, pocket A in yellow and pocket B salmon stick representation. The ligand is drawn in pink and the heme in green stick representation. IDO1 surface‐binding pocket representation. The interactions between epacadostat (magenta sticks) and the two pockets of IDO1 (pocket A and pocket B), as well as the intramolecular H‐bonds are represented by the yellow dashes
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IDO1/inhibitors complexes. (a) IDO1/hydroxylamidine complex (PDBID: 5XE1). Interaction of IDO1 pockets A (yellow sticks) and B (salmon sticks) residues with 35 (orange). The green dash line indicates π–π stack, and the yellow dash line indicates hydrogen bond interaction. Fluorine and chlorine atoms are colored green and light blue, respectively. (b) Key hydrogen bond interactions. IDO1/Aminotriazole derivative complex. Pocket A residues in yellow sticks and pocket B salmon sticks and the ligand, 17, is drawn in cyan. Interactions between aminitriazole 34 (cyan) and the two pockets of IDO1 are depicted in yellow dashes. (c) Pyrrolidine derivative complex (PDBID: 5WHR). The ligand 33 is drawn in orange sticks. IDO1 binding pocket representation (pocket A residues in yellow sticks and pocket B residues in salmon sticks)
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NLG919 analogues. (a) Imidazoleisoindole derivatives 2932. Inhibitor 31 (cyan) with IC50 of 19 nM. Flourine removal resulted in 32 (magenta) and two‐fold decrease in IC50 (38 nM). Other modification resulted in 29 (purple) (279 nM) and 32 (dark blue) that completely lost activity (> 10 μM). (b) IDO1/24 complex. Pockets A (yellow) and B (pink) of IDO1 are occupied by 31 (cyan) that is coordinated with heme group (green) by intramolecular hydrogen bonding with the isoindole nitrogen imidazoleisoindole group. (c) Replacement of the hydroxyl group with carbonyl group (22) (purple) resulted in a 14‐fold decrease in IDO1 inhibitory activity, compared to its hydroxyl analogue 12. (d) When a fluoro group was removed in the imidazoleisoindole to generate 30 (magenta), it showed two‐fold decrease in the inhibition of IDO1 compared to 31. 30 could also make the coordinated covalent bond with the heme iron. (e) Replacement of the five‐membered imidazoleisoindole ring of 30 with a six‐membered, generate 32 (dark blue), resulting in almost complete loss of activity. Hydrogen bonds and π–H bonds are colored in red dash lines
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IDO1:PI:Amg complexes. (a) Structure of IDO1/4PI (PDBID: 2D0T). 4PI (31) (yellow) occupy only the pocket A (yellow). (b) Structure of IDO1/Amg‐1 (PDBID: 4PK5). Amg‐1 (32) (orange) is a larger molecule and can occupy both pockets of IDO1. Interaction of 4PI and Amg1 with IDO1 are displayed in red dashes
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Structure of IDO1 (PDBID: 2D0U). (a) Ribbon representation of the overall structure of human IDO1. The small (teal) and large (dark blue) domains connected by helices L, K, and N (green) and big loop (green) are represented. The 19 helices A‐S are determined based on the primary sequence. (b) Surface and active site of IDO1 are represented. Pocket A (yellow) is the deepest pocket distal to heme group (green) connected to pocket B (salmon)
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cGAMP:STING complex. (a) Overall structure of STING CTT bound to the cGAS product. STING forms a dimer and is colored in orange and teal. (b) cGAMP in yellow sticks binds at a deeper pocket and drags the STING dimer closer to each other, compared to c‐di‐GMP‐bound STING. The base groups of cGAMP are roughly parallel to each other and to four aromatic rings of the Y residues. The bottom ribose ring and the upper purine base groups of cGAMP are coordinated by extensive polar contacts. Hydrogen bonds between c‐di‐GMP and waters are shown as yellow dashed lines. π–π interaction of c‐di‐GMP and Y167 is shown as green dashed line. (c) Structural comparison of the apo‐ and cGAMP‐bound forms of STING. The apo‐STING dimer is colored in dark orange and teal, and it is superimposed against cGAMP‐bound STING dimer colored in light orange and light blue. Conformational changes in STING upon cGAMP binding are observed. (d) Superposition of 3′2′‐cGAMP (yellow sticks) and 2′3′‐cGAMP (dark blue sticks) bound to STING
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STING ligands. cGAMP is the endogenous ligand and contains unprecedented mixed phosphodiester bonds resulting in different isomers. Small molecule DMXAA (28) mSTING inhibitor
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c‐di‐GMP:STING complex. (a) c‐di‐GMP binds into the through at the dimer interface. The complex structure of STING CTT with c‐di‐GMP. c‐di‐GMP is shown as yellow sticks. The STING dimer is shown in an orientation similar to that showed in Figure a. (b) Surface and close‐up view of specific recognition of c‐di‐GMP by STING and details of hydrogen bonds. The interactions between ribose‐phosphate of GMP and waters, as well as c‐di‐GMP and T263 from STING monomer. Hydrogen bonds between c‐di‐GMP and waters are shown as yellow dashed lines and red spheres, respectively. π–π interaction of c‐di‐GMP and Y167 is shown as green dashed line. Residues from STING monomer a that interact with c‐di‐GMP are shown as orange sticks. C‐di‐GMP is shown as yellow sticks. (c) Superposition of the STING/c‐di‐GMP complex with the free STING dimer. The STING protomers in the complex are colored in light orange and light blue, while those in the free STING are in dark orange and teal
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