Table 2.
Structure-based drug design methodologies reported for ligands targeting GPCRs potentially involved in PD.
| Dopamine D2 Receptor (D2R) Agonists | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Entry | Method(s) | Ligand(s) | Relevant Ligand-receptor Interactions | ||||||||
| 1 | Docking onto D2R model using AutoDock 3.0.5 software package [401] (Template: X-ray structure of human β2AR; PDBid 2RH1 [272]) | Dopamine, 2-(aminomethyl)chromans | Dopamine: salt bridge interactions involving Asp114; hydrogen bond interactions with Ser193 and Ser197; π-π interactions involving Trp245, Phe248, and Phe249. 2-(Aminomethyl)chromans: salt bridge interactions involving Asp114; π-π interactions with Phe248; hydrogen bond interactions involving Ser193, Ser194, and/or Ser197 residues [402]. |
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| 2 | Docking onto D2R model using MOE software package [403] (Template: X-ray structure of human β2AR; PDBid 2RH1 [272]) | (R)-(-)-2-OH-NPA | R-(-)-2-OH-NPA: salt bridge interactions involving Asp114; hydrogen bond interactions with Asn186, Ser193, and Ser393; hydrophobic interactions involving Thr412 and π-π interactions with Phe390 [404]. | ||||||||
| 3 | Docking onto D2R model using GLIDE module from Schrödinger Suite [405-407] (Template: X-ray structure of D3R; PDBid 3PBL [294]) | Substituted piperidines, (2-methoxyphenyl) piperazines | Substituted piperidines: salt bridge interactions involving Asp114; π-π interactions with Phe393, His397, and the hydrophobic pocket composed by Phe386, Trp390, and Tyr420; hydrogen bond interactions with Ser193. (2-Methoxyphenyl) piperazines: salt bridge interactions involving Asp114; π-π interactions with Phe394 and the hydrophobic pocket composed by Phe386, Trp390, and Tyr420 [408]. |
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| 4 | Docking onto D2R model using GLIDE module of Schrödinger Suite [405-407] (Template: X-ray structure of D3R; PDBid 3PBL [294]) | 1-(2-Methoxyphenyl)-4-(1-phenethylpiperidin-4-yl)piperazines, 1-(2-methoxyphenyl)-4-[(1-phenethylpiperidin-4-yl)methyl]-piperazines | 1-(2-Methoxyphenyl)-4-(1-phenethylpiperidin-4-yl)piperazines: hydrophobic interactions with the hydrophobic pocket formed by Phe386, Trp390, and Tyr42 residues; salt bridge interactions involving Asp114; hydrogen bond interactions involving Asp114, Ser194, and Ser197 residues. Two possible binding conformations for 1-(2-Methoxyphenyl)-4-[(1-phenethylpiperidin-4-yl)methyl]-piperazines: (i) arylpiperazine moiety interacts with hydrophobic pocket of orthosteric binding site and the head part makes hydrogen bond interactions with Ser194 and Ser197; (ii) the head part interacts with hydrophobic pocket and arylpiperazine group makes hydrogen bond interactions with Ser194 and Ser197 [409]. |
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| 5 | Docking onto D2LR model using AutoDock Vina [410] and AutoDock 4.2 [411] softwares (Template: X-ray structure of D3R; PDBid 3PBL [294]) | (R)-7-OH-DPAT, (R)-7-OH-PIPAT, pramipexole, ropinirole, rotigotine, quinpirole, dopamine, PD128907 and cis-8-OH-PBZI | Hydrogen bond interactions involving Asp114, Val190, Ser193, and Ser194 residues; hydrophobic interactions involving Phe110, Val111, Val115, Ile184, Trp386, Phe389, Phe390, His393, Gly415, and Tyr416 residues [412]. | ||||||||
| 6 | Docking onto D2R model using AutoDock 3.0 software [401] (Template: X-ray structure of bovine RHO; PDBid 1F88 [231]) | Raclopride, L-741,626 | Raclopride: hydrogen bond interactions involving Asp114, Cys118, and Thr119; hydrophobic interactions with a hydrophobic region mainly composed by Tyr408 and Phe410 residues. L-741,626: Salt bridge interactions involving Asp114; hydrogen bond interactions with Ser221 and Thr412; π-π interactions involving Phe389 and Phe411 residues [413]. |
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| 7 | Docking onto D2R model using Docking module of INSIGHT II software (Accelerys Inc., Cambridge, UK) [414] (Template: X-ray structure of bovine RHO; PDBid 1F88 [231]) | 5-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethoxy)-1,3-dihydro-2H-benzimidazole-2-thione | 5-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethoxy)-1,3-dihydro-2H-benzimidazole-2-thione: salt bridge interactions involving Asp 86; hydrogen bond interactions with Trp115, Ser122, Ser141, Phe185, and His 189; π-π interactions involving Phe 178, Trp182, and Tyr216 residues [415]. | ||||||||
| 8 | Docking onto D2R using LIBDOCK module from Discovery Studio software [416] (Template: X-ray structure of bovine RHO; PDBid 1F88 [231]) | Arylpiperazines | Arylpiperazines: hydrophobic interactions involving Leu125, Leu126, Phe144, Val146, and Ile190 residues; hydrogen bond interactions involving Asn135 and Asn141; π-π interactions with Phe144 and His189 residues [417]. | ||||||||
| Dopamine D3 Receptor (D3R) Agonists | |||||||||||
| Entry | Method(s) | Ligand(s) | Results/Conclusions | ||||||||
| 9 | Docking onto D3R model performed by CERIUS2 software (version 4.6) [418] (Template: X-ray structure of bovine RHO; PDBid 1F88 [231]) | (R)-(+)-7-OH-DPAT | R-(+)-7-OH-DPAT: salt bridge interactions involving Asp110; hydrogen bond interactions with Ser192; hydrophobic interactions with Phe106, Val107, Val111, Cys114, Phe345, Phe346, and Tyr373 residues [419]. | ||||||||
| Dopamine D3 Receptor (D3R) Agonists | |||||||||||
| Entry | Method(s) | Ligand(s) | Results/Conclusions | ||||||||
| 10 | Docking onto X-ray structure of D3R (PDBid 3PBL [294]) using AutoDock Vina [410] and AutoDock 4.0 softwares [420, 421] | Glycyrrhetinic acid, E.resveratroloside, curcumin, hirsutanonol, glabridin, alloin, diacerein, bromocriptine, apomorphine, ropinirole | Hydrogen bond interactions with Asp110, Ser192, His349, Thr369, and Tyr373 residues; hydrophobic interactions involving the binding pocket Asp110, Ile183, Ser192, Phe346, His349, Thr369, and Tyr373 [422]. | ||||||||
| 11 | Docking onto X-ray structure of D3R (PDB id 3PBL [294]) using SurFlex Dock software method of SYBYL-X 1.3 package [423] | (E)-N-((1S,4r)-4-(2-(((S)-2-Amino-4,5,6,7-tetrahydro benzo[d]thiazol-6-yl)(propyl)amino)ethyl)cyclohexyl)-3-(4-chlorophenyl)acrylamide, N-((1S,4r)-4-(2-(((S)-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl) amino)ethyl)cyclohexyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide, N-((1S,4r)-4-(2-(((S)-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)ethyl) cyclohexyl)-2-chloropyridine-3-sulfonamide | (E)-N-((1S,4r)-4-(2-(((S)-2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)ethyl) cyclohexyl)-3-(4-chlorophenyl)acrylamide: hydrogen bond interactions with Asp110 and Ile183; van der Waals interactions with Phe106, Phe345, Tyr365, and Tyr373 residues; hydrophobic interactions involving Ser182, Phe345, and Ser366 residues. N-((1S,4r)-4-(2-(((S)-2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)ethyl) cyclohexyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide: hydrogen bond interactions with Asp110 and Ile183; hydrophobic interactions involving Val111, Ser182, Ile183, Val189, Ser192, Phe345, Phe346 residues. N-((1S,4r)-4-(2-(((S)-2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)ethyl) cyclohexyl)-2-chloropyridine-3-sulfonamide: hydrogen bond interactions with Glu90 and Ser192; hydrophobic interactions with Asp110, Ser182, Ile 183, Phe345, Phe346, and Tyr373 residues [424]. |
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| 12 | Docking onto X-ray structure of D3R (PDB id 3PBL [294]) using AutoDock Vina [410] and AutoDock 4.2 [411] softwares | R-7-OH-DPAT, R-7-OH-PIPAT, pramipexole, ropinirole, rotigotine, quinpirole, dopamine, PD128907 and cis-8-OH-PBZI | Hydrogen bond interactions involving Asp110, Val111, Thr115, Ser192, and Ser196 residues; hydrophobic interactions with Phe106, Val107, Val111, Ile183, Phe188, Trp342, Phe345, Phe346, His349, Thr369, and Tyr373 residues [412]. | ||||||||
| 13 | Docking onto X-ray structure of D3R (PDB id 3PBL [294]) using InducedFit docking software [425-427] | [4-(4-Carboxamidobutyl)]-1-arylpiperazines | N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)-piperazin-1-yl)butyl)imidazo[1,2-a]pyridine-2-carboxamide: hydrogen bond interactions involving Thr115 and Ser196; hydrophobic interactions with Ile183, Val189, and Val350 residues. The arylamide moiety of this ligand and other analogues may adopt three different conformations: (i) the arylamide group is docked onto Glu90; (ii) the arylamide moiety is placed in proximity to Val180 and Ser182 residues; (iii) the arylamide moiety is involved in π-π interactions with Tyr365 and in hydrogen bond interactions with Thr369 [66]. | ||||||||
| Adenosine A2A receptor (A2AAR) antagonists | |||||||||||
| Entry | Method(s) | Ligand(s) | Results/Conclusions | ||||||||
| 14 | Docking onto A2AAR model using MOE software [428] (Template: X-ray structure of A2AAR; PDBid 3EML [44]) | 8-Substituted 9-ethyladenine derivatives | Two different ligand binding orientations towards A2AAR, interacting with key residues Phe163, Glu164, and Asn248 of A2AAR model (corresponding to Phe168, Glu169, and Asp253 of human A2AAR). Ligand binding orientation 1: π-π interactions involving Phe163; hydrogen bond interactions with Glu164 and Asn248. Ligand binding orientation 2: π-π interactions involving Phe163; hydrogen bond interactions with Asn248 [96]. | ||||||||
| 15 | Docking onto X-ray structure of A2AAR (PDBid 4EIY [244]) using AutoDock 4.2 software [411] | 3-[4-Amino-6-(2-chlorobenzyl)thieno[2,3-d] pyrimidin-2-yl]benzonitrile | 3-[4-Amino-6-(2-chlorobenzyl)thieno[2,3-d]pyrimidin-2-yl]benzonitrile: hydrophobic interactions involving Leu190, Leu194, Tyr197, Phe201, Ala236, Val239, and Ala243 residues [429]. | ||||||||
| 16 | Docking onto X-ray structure of A2AAR (PDBid 3EML [44]) using GLIDE module from Schrödinger suite [405-407] | 10 ligands with the best docking scores selected from a library of 46 A2AAR antagonists | Hydrogen bond interactions involving Asn253 for all ligands and Ile180, Ala81, and Tyr271 residues for some ligands; π-π interactions with Phe168 [430]. | ||||||||
| 17 | Docking onto X-ray structure of A2AAR (PDBid 3EML [44]) using DOCK 5.4 software [431] | 7-Substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines, piperazine derivatives of triazolotriazine and triazolopyrimidines | 7-Substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines: hydrogen bond interactions involving Thr88; π-π interactions involving Phe182 and Phe257 residues; hydrophobic interactions with Ile66, Ile92, Ile244, and Trp276 residues. Piperazine derivatives of triazolotriazine and triazolopyrimidines: hydrogen bond interactions involving Thr27; π-π stacking interactions with Phe182; hydrophobic interactions involving Ile92, Phe93, and Val186 residues [432]. |
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| Dopamine D3 Receptor (D3R) Agonists | |||||||||||
| Entry | Method(s) | Ligand(s) | Results/Conclusions | ||||||||
| 18 | Docking onto X-ray structure of A2AAR (PDBid 4EIY [244]) using GLIDE module from Schrödinger suite [405-407] | 5’-Substituted amiloride derivatives | 5’-Substituted amiloride derivatives: hydrogen bond and salt bridge interactions with Asn52 and Thr88; π-π interactions with Trp246; hydrophobic interactions with Phe168, Met177, Leu249, and Ile274 residues [433]. | ||||||||
| 19 | Docking onto A2AAR model using GLIDE module from Schrödinger suite [405-407] (Template: X-ray structure of β1AR; PDBid 2VT4 [262]) | 4-(3-Aminoamino-5-phenyl-1,2,4-triazin-6-yl)-2-chlorophenol, 6-(2,6-dimethylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine | 4-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-2-chlorophenol: hydrogen bond interactions involving Asn253 and His278; π-π interactions with Phe168, and hydrophobic interactions involving Met270. 6-(2,6-Dimethylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine: hydrogen bond interactions involving Asn253; π-π interactions with Phe168; and hydrophobic interactions with Met270, with a pocket comprised by Leu84, Leu85, Met177, Asn181, Trp246, Leu249, and His250 and a pocket formed by Ala63, Ile66, Ser277, and His278 residues [243]. |
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| 20 | Docking onto A2AAR model using FlexiDock utility in the Biopolymer module of SYBYL 6.7.1 (Tripos, St Louis, MO) [434] (Template: X-ray structure of RHO; PDBid 1BRD [435]) | CGS15943 | CGS15943: hydrophobic interactions between quinazoline ring and Leu85, Ile135, Leu167, Phe168, Phe182, Val186, Trp246, and Leu249, and between furan ring and Ile80, Val84, and Ile274; hydrogen bond interactions involving Asn181 and Asn253 residues [436]. | ||||||||
| 21 | Docking onto X-ray structure of A2AAR (PDBid 3EML [44]) using GLIDE module from Schrödinger suite software [405-407], InducedFit docking software [425-427], and ICM molecular modeling software (Molsoft, LLC) [437] | ZM241385 | ZM241385: hydrogen bond interactions involving Glu169 and Asn253 residues; hydrophobic interactions with Phe168, His264, Ile267, Met270, and Ile274 residues [438-440]. | ||||||||
| 22 | Docking onto A2AAR model using GLIDE module from Schrödinger suite software [405-407] and InducedFit docking software [425-427] (Template: X-ray structure of β2AR; PDBid 2RH1 [272]) | ZM241385 | ZM241385: hydrogen bond interactions involving Asn253; hydrophobic interactions with Leu85, Thr88, Trp246, and Leu249 residues; π-π interactions with Phe168 [438]. | ||||||||
| 23 | Docking onto X-ray structure of A2AAR (PDBid 3EML [44]) using AutoDock Vina program [411]. | Caffeine | Five binding poses of caffeine to A2AAR were analysed and the most relevant residues involved in caffeine-A2AAR interaction are: Ala63, Val84, Leu85, Thr88, Phe168, Glu169, Met177, Trp246, Leu249, His250, Asn253, Ile274, and His278 [441]. | ||||||||
| 24 | Docking onto A2AAR model using CAChe 6.1 [442] and CAChe 7.5 softwares [442] (Template: X-ray structures of bovine RHO and β2AR; PDBid 1U19 [332] and 2RH1 [272]) | XAC, KW6002, ZM241385 | In bovine rhodopsin, the purine ring of XAC and the phenyl rings of KW6002 and ZM241385 are accommodated in a pocket formed by Leu85, Thr88, Gln89, Ile135, Leu167, Phe168, Val178, Asn181, and Phe182. The purine ring of KW6002 and ZM241385 and the aminoethylphenoxyacetamid group of XAC occupies a pocket comprised by Glu13, Val55, Ile60, Ala63, Phe80, Ile274, Ile275, and His278. The furan moiety of ZM-241385 interacts with a lipophilic pocket formed by Phe62, Ile66, and Val164. In β2AR, the purine ring of ligands is accommodated in a pocket formed by Leu48, Ala51, Asp52, Leu87, Thr88, Ser91, Leu95, Ile238, Phe242, Trp246, His250, Ser277, His278, Asn280, Ser281, and Asn285. The aromatic rings are placed in a pocket comprised by Val55, Ala59, Val60, Phe62, Ala63, Val84, Gln89, Glu169, Trp246, Ile274, and His278. XAC makes hydrogen bond interactions with Glu169, Ser277, His278, and Ser281 residues [443]. |
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| 25 | Docking onto a theoretical model of A2AAR (PDBid 1MMH) using DOCK 5.4 software [431] | Xanthine derivatives (KW6002, KF17837, BS-DMPX) Non-xanthine derivatives (7-substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines and piperazine derivatives of [1,2,4]triazolo[1,5-a]triazine) |
Xanthine derivatives: hydrogen bond interactions involving Ser277; π-π interactions involving Tyr179, His250, and Phe257 residues; hydrophobic interactions with hydrophobic domains located at the entrance and at the bottom of binding pocket formed by Ser91, Ile92, Trp246, Leu249, Ala273, and His278 residues. Non-xanthine derivatives: hydrogen bond interactions involving Thr88 and Thr271 residues; π-π interactions involving Phe82 and Phe257 residues. The furan ring accomodates in a hydrophobic pocket comprised by Ile66, Ile92, Ile244, and Trp276 in 7-substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines and in a hydrophobic pocket comprised by Ile92, Phe93, and Val186 in piperazine derivatives of [1,2,4]triazolo[1,5-a]triazine) [444]. |
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| Dopamine D3 Receptor (D3R) Agonists | |||||||||||
| Entry | Method(s) | Ligand(s) | Results/Conclusions | ||||||||
| 26 | Docking onto TM2, TM3, TM5, TM6, and TM7 domains of A2AAR (PDBid 3PWH [241]) performed by Autodock using Lamarckian Genetic Algorithm [401] | Pyrimidine and triazine derivatives, pyrazolo[3,4-d]pyrimidines, pyrrolo[2,3-d]pyrimidines, triazolo[4,5-d]pyrimidines, 6-arylpurines, thieno[3,2-d]pyrimidines | Hydrogen bond interactions involving Glu169 and Asn253 residues; hydrophobic interactions with Val84, Leu249, Met270 and Ile274; π-π interactions with Phe168 of A2AAR [445]. | ||||||||
| 27 | Docking onto X-ray structure of A2AAR (PDBid 3PWH [241]) using GLIDE module from Schrödinger suite [405-407] | 2-(Furan-2-yl)-[1,2,4]triazolo[1,5-f]pyrimidin-5-amines, 2-(furan-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amines, 2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amines | Hydrogen bond interactions involving Glu169 and Asn253 residues; π-π interactions with Phe168 and His250. Weak interactions with Ser67 (hydrogen bond interactions) and Tyr271 (π-π interactions) for some derivatives [446]. | ||||||||
| M1 muscarinic acetylcholine receptor (mAChR1) antagonists / negative allosteric modulators (NAMs) | |||||||||||
| Entry | Method(s) | Ligand(s) | Results/Conclusions | ||||||||
| 28 | Docking onto X-ray structure of mAChR1 (PDBid 5CXV [307]) using GLIDE module from Schrödinger suite [405-407] | Tiotropium | Tiotropium: hydrogen bond interactions involving Asp residue [307]. | ||||||||
| 29 | Docking onto mAChR1 model using DOCK 4.01 [447], FlexX 1.8 [448], and GOLD 1.1 softwares [449] (Template: X-ray structure of bovine RHO; PDBid 1F88 [231]) |
Pirenzepine | Pirenzepine: salt bridge interactions between the basic nitrogen atom and Asp residue at TM3, the lactam ring interacts with Asn residue at TM6 and its aromatic nitrogen atom with Thr residue at TM5 [450]. | ||||||||
| 30 | Docking onto mAChR1 model using GOLD software [449] (Template: X-ray structure of bovine RHO; PDBid 1F88 [231]) | N-Methyl-4-piperidyl benzylates | N-Methyl-4-piperidyl benzylates: salt bridge interactions involving Asp105; hydrophobic interactions involving Tyr404; hydrogen bond interactions with Tyr179 [116]. | ||||||||
| Metabotropic Glutamate Receptor 2 (MGluR2) agonists / positive allosteric modulators (PAMs) | |||||||||||
| Entry | Method(s) | Ligand(s) | Results/Conclusions | ||||||||
| 31 | Docking onto mGluR2 model using GLIDE module from Schrödinger suite [405-407] (Template: X-ray structures of mGluR1, mGluR5, and β2AR (PDBid 4OR2 [377], 4OO9 [381], and 3SN6 [277]) | JNJ-42153605 | JNJ-42153605: hydrophobic interactions involving Leu639, Phe643, Leu732, Trp773, and Phe776 residues; hydrogen bond interactions involving Ser731 and Asn735; π-π interactions with His723 [451]. | ||||||||
| 32 | Docking onto X-ray structure of mGluR2 (PDBid 5CNJ [379]) using MOE v. 2013.08 [452] | LY2812223 | LY2812223: salt bridge interactions involving Arg61, Asp295, and Lys377 residues; hydrogen bond interaction involving Ser165, Ala 166, Thr168, and Glu273 residues; water-mediated hydrogen bond interactions with Asp301; π-H interactions with the Ser272 [379]. | ||||||||
| Metabotropic Glutamate Receptor 3 (MGluR3) agonists / positive allosteric modulators (PAMs) | |||||||||||
| Entry | Method(s) | Ligand(s) | Results/Conclusions | ||||||||
| 33 | Docking onto X-ray structure of mGluR3 (PDBid 2E4U [380]) using Induced Fit algorithm [425-427] | Glutamate | Glutamate: hydrogen bond interactions with Ser151, Ala172, Ser173, and Thr174 residues; salt bridge interactions involving Arg64, Arg68, Asp301, and Lys389 residues [453]. | ||||||||
| 34 | Docking onto X-ray structures of mGluR3 (PDBid 2E4V [380], 2E4W [380], 2E4X [380], and 2E4Y [380]) | DCG-IV, 1S,3S-ACPD, 1S,3R-ACPD, 2R,4R-APDC | DCG-IV: hydrogen bond interactions involving Arg68, Ser151, Ala172, Thr174, Tyr222, Ser278, Asp301, and Lys389; water-mediated hydrogen bond interactions with Arg64; van der Walls interactions involving Tyr150. 1S,3S-ACPD: hydrogen bond interactions involving Arg68, Ser151, Ala172, Thr174, Asp301, and Lys389; water-mediated interactions with Arg64 and Ser278; van der Waals interactions involving Tyr222 and Gly302. 1S,3R-ACPD: hydrogen bond interactions involving Arg68, Ser151, Ala172, Thr174, Asp301, and Lys389; van der Waals interactions with Tyr222 and Gly302. 2R,4R-APDC: hydrogen bond interactions involving Arg68, Ser151, Ala172, Thr174, Asp301, and Lys389; van der Waals interactions with Tyr222 [380]. |
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| Metabotropic Glutamate Receptor 4 (MGluR4) agonists / positive allosteric modulators (PAMs) | |||||||||||
| Entry | Method(s) | Ligand(s) | Results/Conclusions | ||||||||
| 35 | Docking onto mGluR4 model using AutoDock 3.0 software [401] (Template: X-ray structure of mGluR1; PDBid 1EWK [378]) | L-Glutamate, L-AP4, S-PPG | L-Glutamate, L-AP4, and S-PPG interact with the agonist binding site of mGluR4 composed by Arg78, Ser159, and Thr182 [454]. | ||||||||
| 36 | Docking onto VFT domain of mGluR4 using Discovery Studio 2.5.5 software (Accelerys Inc., Cambridge, UK) [455] | LSP4-2022 | The hydroxybenzilic moiety of LSP4-2022 interacts with Lys74 and Lys317 and the glutamate-like moiety interacts with Arg78, Ser159, Ala180, Thr182, Tyr230, Asp312, and Lys405. The phenoxyacetic acid group of LSP4-2022 is involved in hydrogen bond interactions with Thr108, Ser157, and Gly158 [456]. | ||||||||
| 37 | Docking onto mGluR4 model using Discover 3.0 and WHATIF softwares [413] (Template: X-ray structures of LIVBP, LBP, and AmiC; PDBid 2LIV [457], 2LBP [458], and 1PEA [459]) | ACTP-I | Docking to the open form of mGluR4 model, built from LIVBP and LBP templates, has shown that ACTP-I interacts with Lys74, Arg78, Ser159, and Thr182. Docking to the closed form of mGluR4 model, built from AmiC template, has shown that ACTP-1 interacts with Tyr230, Asp312, Ser313, and Lys317 [460]. | ||||||||
| Metabotropic Glutamate Receptor 5 (MGluR5) antagonists / negative allosteric modulators (NAMs) | |||||||||||
| Entry | Method(s) | Ligand(s) | Results/Conclusions | ||||||||
| 38 | Docking onto X-ray structure of mGluR5 (PDBid 4OO9 [381]) using Maestro v.9.3 (Schrodinger) software [461] | Mavoglurant | Mavoglurant: hydrogen bond interactions involving Ser805, Ser809, and Asn747 residues; hydrophobic interactions involving two pockets (one hydrophobic pocket formed by Gly624, Ile625, Gly628, Ser654, Pro655, Ser658, Tyr659, Val806, Ser809, Ala810, and Ala813 residues, and other hydrophobic pocket consisted of Ile651, Val740, Pro743, and Leu744 residues) [381]. | ||||||||
| 39 | Docking onto X-ray structure of mGluR5 (PDBid 5CGC [382], 5CGD [382]) using PyMOL (Schrodinger) [462] | 3-Chloro-4-fluoro-5-[6-(1H-pyrazol-1-yl) pyrimidin-4-yl]benzonitrile, HTL14242 | 3-Chloro-4-fluoro-5-[6-(1H-pyrazol-1-yl) pyrimidin-4-yl]benzonitrile: hydrogen bond interactions involving Ser809; water-mediated hydrogen bond interaction with Val 740; π-π interactions with Trp785 and Phe788 residues. HTL14242: hydrogen bond interactions involving Ser809; water-mediated hydrogen bond interaction with Val 740; π-π interactions with Tyr659, Trp785, and Phe788 residues. The pyrazole and pyridyl rings of 3-chloro-4-fluoro-5-[6-(1H-pyrazol-1-yl) pyrimidin-4-yl]benzonitrile and HTL14242, respectively, are docked onto a pocket defined by Ile625, Gly628, Ser654, Pro655, Ser658, Tyr659 and Ser809. The pyrimidine linker of both ligands is located in a pocket formed between Pro655, Tyr659, Val806, and Ser809 residues [382]. |
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| 40 | Docking onto X-ray structure of mGluR5 (PDBid 4OO9 [381]) using CDocker [463] in Discovery Studio 3.1 (Accelrys Inc., Cambridge, UK) | 4-Bromo-N-(3-bromophenyl)thiazole-2-carboxamide, 4-bromo-N-(6-methylpyridin-2-yl)thiazole-2-carboxamide | 4-Bromo-N-(3-bromophenyl)thiazole-2-carboxamide: hydrogen bond interactions involving Tyr659; hydrophobic interactions involving two pockets (one hydrophobic pocket formed by Gly624, Ile625, Gly628, Ser654, Pro655, Ser658, Tyr659, Val806, Ser809, Ala810, and Ala813 residues, and other hydrophobic pocket defined by Pro655, Tyr659, Val806, and Ser809 residues. 4-Bromo-N-(6-methylpyridin-2-yl)thiazole-2-carboxamide: hydrogen bond interactions involving Tyr659; hydrophobic interactions with Ile625, Pro655, Ala810, and Ala813 residues [446] [464]. |
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| 41 | Docking onto X-ray structure of mGluR5 (PDBid 4OO9 [381]) using CDocker software [463] | Aglaiduline, 5-O-ethyl-hirsutanonol, yakuchinone A | Aglaiduline: hydrophobic interactions involving two pockets (one hydrophobic pocket formed by Arg648, Ile651, Val740, and Pro743 residues, and other hydrophobic pocket defined by Ser654, Pro655, and Ala810 residues; hydrogen bond interactions involving Asn747. Yakuchinone A: hydrophobic interactions involving two pockets (one hydrophobic pocket formed by Arg648, Ile651, Val740, and Pro743 residues, and other hydrophobic pocket defined by Ser654, Pro655, and Ala810); hydrogen bond interactions involving Ser805. 5-O-Ethyl-hirsutanonol: hydrogen bond interactions involving Ser805 and Ser809 [465]. |
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| 42 | Docking onto mGluR5 model using AutoDock 3.0.5 software [401] (Template: X-ray structures of mGluR1; PDBid 1EWK [378], 1EWV [378], 1EWT [378]) | S4-CPG, MCPG | Hydrogen bond interactions involving Tyr43, Ser152, and Thr154 residues [466]. | ||||||||
| 43 | Docking onto mGluR5 model using ROSETTA v3.4 software [467] (Template: X-ray structures of β2AR, S1PR1, and D3R; PDBid 2RH1 [272], 3V2Y [357], and 3PBL [294]) | CHPyEPC, 1,4-BisPEB, MPEP, 1,3-BisPEB | All NAM ligands make interactions with Leu630, Ile651, Gly652, Pro655, Trp785, Phe788, Tyr792, Val806, and Ser809 residues. CHPyEPC, 1,4-BisPEB, and 1,3-BisPEB interact with Val740, Pro743, Leu744, and Asn747 residues [468]. | ||||||||
| 5-Hydroxytryptamine Receptor 1A (5-HT1AR) Agonists | |||||||||||
| Entry | Method(s) | Ligand(s) | Results/Conclusions | ||||||||
| 44 | Docking onto 5-HT1AR model using Affinity module from INSIGHT II software [414] (Template: X-ray structures of RHO; PDBid 1F88 [231], 1HZX [328], and 1L9H [330]) | N1-Substituted N-arylpiperazines | N1-Substituted N-arylpiperazines: salt bridge interactions involving Asp116; π-π interactions involving Phe361 and Tyr390 residues; hydrogen bond interactions with Thr188. Some ligands are involved in π-π interactions with hydrophobic pocket formed by Phe204, Leu 359, and Phe362 [469]. | ||||||||
| 45 | Docking onto 5-HT1AR model using Affinity module from INSIGHT II software [414] (Template: X-ray structures of RHO; PDBid 1F88 [231], 1HZX [328], and 1L9H [330]) | 1-Cinnamyl-4-(2-methoxyphenyl) piperazines | 1-Cinnamyl-4-(2-methoxyphenyl)piperazines: salt bridge interactions involving Asp116; π-π interactions involving Phe361 and Tyr390 residues; hydrogen bond interactions with Thr188 [470]. | ||||||||
| 46 | Docking onto 5-HT1AR model using Affinity from INSIGHT II software [414] (Template: X-ray structures of RHO; PDBid 1F88 [231], 1HZX [328], and 1L9H [330]) | 4-Halo-6-[2-(4-arylpiperazin-1-yl)ethyl]-1H-benzimidazoles | 4-Halo-6-[2-(4-arylpiperazin-1-yl)ethyl]-1H-benzimidazoles: salt bridge interactions involving Asp116; hydrogen bond interactions involving Ser199 and Trp358; π-π interactions involving Phe361 and Tyr390 residues [471]. | ||||||||
| 47 | Docking onto 5-HT1AR model using FlexX-Pharm from SYBYL 7.0 software [472] (Template: X-ray structure of bovine RHO; PDBid 1F88 [231]) | Arylpiperazines | Arylpiperazines: salt bridge interactions involving the Asp residue; π-π interactions with the Phe residue; hydrogen bond interactions with Asn, Cys, Ser, Thr, and Tyr residues [473]. | ||||||||
| 48 | Docking onto 5-HT1AR model using AutoDock 3.0.5 software [401] (Template: X-ray structure of RHO; PDBid 2R4R [271]) | 1-(Benzo[b]thiophen-2-yl)-3-(4-arylpiperazin-1-yl)-propan-1-one derivatives | 1-(Benzo[b]thiophen-2-yl)-3-(4-pyridin-2-yl)-piperazin-1-yl)-propan-1-one: salt bridge and hydrogen bond interactions involving Asp116; ion-dipole interactions with Asn385; π-π interactions involving Phe361 [474]. | ||||||||
| 49 | Docking onto 5-HT1AR model using GOLD 4.0 software [449] (Template: X-ray structure of β1AR; PDBid 2Y03 [263]) | Carboxamide and sulfonamide alkyl piperazine analogues | Carboxamide and sulfonamide alkyl piperazine analogues: salt bridge interactions involving Asp116; hydrogen bond interactions with Ser199 and Thr200; π-π interactions involving Tyr96, Phe361, Phe362, Trp387, and Tyr390 residues [475]. | ||||||||
| 50 | Docking onto 5-HT1AR model using AutoDock 4.0 software [411] (Template: X-ray structure of β2AR; PDBid 3P0G [276]) | 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1H-indole derivatives | 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1H-indole derivatives: salt bridge interactions involving Asp116; π-π interactions with Phe and Tyr residues; hydrogen bond interactions with the Ser residue [476]. | ||||||||
| 5-Hydroxytryptamine receptor 2A (5-HT2AR) antagonists | |||||||||||
| Entry | Method(s) | Ligand(s) | Results/Conclusions | ||||||||
| 51 | Docking onto 5-HT2AR model using QXP software [477] (Template: X-ray structure of bovine RHO; PDBid 1F88 [231]) | (Aminoalkyl)benzo and heterocycloalkanones | (Aminoalkyl)benzo and heterocycloalkanones: hydrogen bond interactions involving Cys148, Asp155, and Ser159; hydrophobic interactions with residues located in TM2 and TM7 [478]. | ||||||||
| 52 | Docking onto X-ray structure of 5-HT2AR (PDBid 2VT4 [262]) using GLIDE module from Schrödinger suite [405-407] | 4-Aryl-2,7,7-trimethyl-5-oxo-N-phenyl- 1,4,5,6,7,8-hexahydroquinoline-3-carboxamides | 4-Aryl-2,7,7-trimethyl-5-oxo-N-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxamides: interaction with Cys199, Asn310, and Asn329 residues [479]. | ||||||||
| 53 | Docking onto 5-HT2AR model using GOLD 4.12 software [449] (Template: X-ray structure of β2AR; PDBid 2RH1 [272]) | Ketanserin, 05245768 | Ketanserin: salt bridge interactions involving the Asp residue; hydrogen bond interactions involving the Ser residue; hydrophobic interactions with Phe and Tyr residues. 05245768: salt bridge interactions involving the Asp residue; hydrogen bond interactions involving the Ser residue; hydrophobic interactions with Ile, Phe, and Tyr residues [480]. |
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| 54 | Docking onto 5-HT2AR model using FlexiDock from SYBYL-X 1.2 software (Tripos, St Louis, MO) [434] (Template: X-ray structure of β2AR; PDBid 2RH1 [272]) | (2R,4S)-PAT, (2S,4R)-PAT, (2R,4S)-4’-Cl-PAT, (2S,4R)-4’-Cl-PAT | (2S,4R)-PAT: salt bridge interactions involving the Asp residue; π-π interactions involving the Phe residue. (2R,4S)-PAT and (2S,4R)-4’-Cl-PAT: salt bridge interactions involving the Asp residue (2R,4S)-4’-Cl-PAT salt bridge interactions involving the Asp residue; hydrogen bond interactions with the Ser residue [481]. |
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| 5-Hydroxytryptamine Receptor 1A (5-HT1AR) Agonists | |||||||||||
| Entry | Method(s) | Ligand(s) | Results/Conclusions | ||||||||
| 55 | Docking onto 5-HT2AR model using GLIDE module from Schrödinger suite [405-407] (Template: X-ray structure of β2AR; PDBid 2RH1 [272]) | Nefazodone, aripiprazole, haloperidol, cyproheptadine, trazodone, clozapine, ketanserin, spiperone, risperidone |
Interaction with a binding pocket comprised by Ile152, Asp155, Val156, Ser207, Met208, Pro211, Leu229, Asp231, Val235, Leu236, Ser239, Phe339, Asn343, and Asn363 residues [482]. | ||||||||
| 56 | Docking onto 5-HT2AR model using AutoDock Vina 1.1.1 [410] (Template: X-ray structure of β2AR; PDBid 3D4S [273]) | Arylpiperazines | Arylpiperazines: salt bridge interactions involving Asp155; hydrogen bond interactions with Asn343; hydrophobic interactions involving two hydrophobic pockets (one hydrophobic pocket comprised by Leu123, Ser159, Trp336, Phe339, Val366, and Tyr370 residues, and the other pocket formed by Trp151, Ile152, Leu229, Ala230, Phe234, and Val235 residues) [483]. | ||||||||
| 57 | Docking onto 5-HT2AR model using ICM Pro docking algorithm [437], GLIDE from Schrödinger suite [405-407], and GOLD programs [449] (Template: X-ray structures of bovine RHO and β2AR; PDBid 1U19 [332] and 2RH1 [272]) | Nantenine analogues | Nantenine analogues: salt bridge interactions involving Asp155; hydrogen bond interactions involving Asn343. The majority of nantenin analogus interacts with Asp155, Val156, Ser159, Ile210, Leu228, Phe234, Gly238, Ser242, and Ile341 residues. Other ligands interact with Ile152, Thr160, Ile163, Ile206, Ser239, Phe243, Ser244, Pro338, Phe339, Phe340, Thr342, Asn343, Met345, Val366, and Gly369 residues [484]. | ||||||||
| 58 | Docking onto 5-HT2AR model using GLIDE module from Schrödinger suite [405-407] (Template: X-ray structure of human A2AAR; PDBid 2YDV [240]) | Ketanserin, risperidone, ziprasidone | Ketanserin: salt bridge and hydrogen bond interactions involving Asp155; hydrogen bond interactions with Trp151; hydrophobic interactions with Phe125 and Val130; van der Waals interactions involving Leu126, Pro129, Leu154, Phe158, Val204, and Met208 residues. Risperidone: salt bridge and hydrogen bond interactions involving Asp155; hydrogen bond interactions with Trp151; van der Waals interactions involving Leu126, Val130, Ile152, Leu154, Phe158, and Met208 residues. Ziprasidone: hydrogen bond interactions involving Trp151; π-π interactions involving Phe158; hydrophobic interactions involving Leu122, Leu126, and Phe158 residues; van der Waals interactions involving Ile118, Phe193, Ile196, Ile197, and Trp200 residues [485]. |
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| 59 | Docking onto 5-HT2AR model using GLIDE module from Schrödinger suite [387-389] (Template: X-ray structure of human A2AAR; PDBid 2YDV [240]) | N-[3-(4-(1H-indol-2-yl)phenoxy)propyl]-4-chlorophenylamine | N-[3-(4-(1H-Indol-2-yl)phenoxy)propyl]-4-chlorophenylamine: hydrogen bond interactions involving Leu362 and Asn363 residues; π-π interactions involving Phe339; hydrophobic interactions with Thr342 and Asn343; van der Waals interactions with Leu136, Ala230, Phe339, Asn343, Ala346, Val347, Glu355 and Val366 residues [485]. | ||||||||
| 60 | Docking onto 5-HT2AR model using AutoDock 4.2 software [411] (Template: X-ray structure of β2AR; PDBid 2RH1 [272]) | (R)-Roemerine | (R)-Roemerine: salt bridge and hydrogen bond interactions involving Asp155; dipole-dipole interactions involving Ser159 and Tyr370, van der Waals interactions involving Ser239, Ala242, Trp336, Phe339, Phe340, Val366, and Tyr370 residues [486]. | ||||||||
| 5-Hydroxytryptamine Receptor 2C (5-HT2CR) Antagonists | |||||||||||
| Entry | Method(s) | Ligand(s) | Results/Conclusions | ||||||||
| 61 | Docking onto 5-HT2CR model using QXP software [477] (Template: X-ray structure of bovine RHO; PDBid 1F88 [231]) | (Aminoalkyl)benzo and heterocycloalkanones | (Aminoalkyl)benzo and heterocycloalkanones: hydrogen bond interactions involving Cys148, Asp155, and Ser159; hydrophobic interactions with residues located in TM2 and TM7 [478]. | ||||||||
| 62 | Docking onto 5-HT2CR model using FlexX software [448] (Template: X-ray structure of β2AR; PDBid 2RH1 [272]) | N-(3-(4-Methylimidazolidin-1-yl)phenyl)-5,6-dihydrobenzo[h]quinazolin-4-amine, N-(4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)-1,2-dihydro-3H-benzo[e] indole-3-carboxamide, 1-(3,5-difluoro phenyl)-3-(4-methoxy-3-(2-(piperidin-1-yl)ethoxy)phenyl) imidazolidin-2-one, N-(3-(2-((3-(piperazin-1-yl)pyrazin-2-yl) oxy)ethoxy) benzyl)propan-2-amine | Hydrophobic interactions involving Val106, Val135, Phe137, Phe214, Val215, Val221, Ala222, Phe223, Trp324, Phe327, Phe328, Leu350, and Leu354 residues. N-(3-(4-Methylimidazolidin-1-yl)phenyl)-5,6-dihydrobenzo[h]quinazolin-4-amine: hydrogen bond interactions with Asp134 and Arg195 residues. N-(4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl)-1,2-dihydro-3H-benzo[e]indole-3-carboxamide: hydrogen bond interactions involving Asp134 and Tyr358 residues. 1-(3,5-Difluorophenyl)-3-(4-methoxy-3-(2-(piperidin-1-yl)ethoxy)phenyl) imidazolidin-2-one: hydrogen bond interactions involving Arg195 and Tyr358 residues. N-(3-(2-((3-(Piperazin-1-yl)pyrazin-2-yl)oxy)ethoxy)benzyl)propan-2-amine: hydrogen bond interactions involving Arg195, Val208, Asn351, and Tyr358 residues [487]. |
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| 5-Hydroxytryptamine Receptor 2C (5-HT2CR) Antagonists | |||||||||||
| Entry | Method(s) | Ligand(s) | Results/Conclusions | ||||||||
| 63 | Docking onto 5-HT2CR model using FlexiDock from SYBYL-X 1.2 software (Tripos, St Louis, MO) [434] (Template: X-ray structure of β2AR; PDBid 2RH1 [272]) | (2R,4S)-PAT, (2S,4R)-PAT, (2R,4S)-4’-Cl-PAT, (2S,4R)-4’-Cl-PAT | (2S,4R)-PAT: salt bridge interactions involving the Asp residue; π-π interactions involving the Phe residue. (2R,4S)-PAT and (2S,4R)-4’-Cl-PAT: salt bridge interactions involving the Asp residue (2R,4S)-4’-Cl-PAT salt bridge interactions involving the Asp residue; hydrogen bond interactions with the Ser residue [481]. |
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| 64 | Docking onto 5-HT2CR model using GLIDE module from Schrödinger suite [387-389] [405-407] (Template: X-ray structure of β2AR; PDBid 2RH1 [272]) | (E)-3-(2-chlorophenyl)-1-(5-methoxy-6-(2-(piperidin-1-yl)ethoxy)indolin-1-yl)prop-2-en-1-one | (E)-3-(2-chlorophenyl)-1-(5-methoxy-6-(2-(piperidin-1-yl)ethoxy)indolin-1-yl)prop-2-en-1-one: salt bridge interactions involving Asn331, Ser334 and Val354 residues; hydrogen bond interactions involving Asn331; hydrophobic interactions involving Val135, Val208, Phe214, Ala222, Phe327, Phe328, and Val354 residues [488]. | ||||||||