Summary of molecular docking screening results using experimental GPCR structures of the target. Screens focused on hit optimization were omitted.
| Target(s) (Antitarget) | Reference | Screened Structure(s)a | Docking and Scoringb | Number Docked cmpds | Source of Chemical Library (Type)c | Screening goal | Tested cmpds | Hits (≤ 10 µM)d | Ligand Hit Rate (≤ 10 µM)d | Best Affinity/ Activitye |
|---|---|---|---|---|---|---|---|---|---|---|
| Adenosine receptors | ||||||||||
| A1R | (Wei et al., 2020) | 5N2S | Glide | 19K | Chemical supplier: ChemDiv (DL) | Ligands | 22 | 18 (11) | 82% (50%) | pKi = 7.13 |
| A2AR | (Carlsson et al., 2010) | 3EML | DOCK | 1.4M | ZINC (LL) | Ligands | 20 | 7 | 35% | Ki = 200 nM |
| A2AR | (Katritch et al., 2010) | 3EML | ICM | 4.3M | Molsoft Screenpub (DL) | Ligands | 56 | 23 | 41% | Ki = 32 nM |
| A2AR | (Chen et al., 2013a) | 3EML | DOCK | 328K | ZINC (FL) | Ligands | 22 | 14 (4) | 64% (18%) | Ki = 2200 nM |
| A2AR | (Rodriguez et al., 2015) | 3EML, 3QAK, 2YDO, 2YDV | DOCK | 6.7M | ZINC (LL) | Agonists | 20 | 9 | 45% | Ki = 16 nM |
| A2AR | (Rodriguez et al., 2016) | 2YDO | DOCK | 7K | Virtual library (LL) | Agonists | 13 | 2 | 15% | Ki = 495 nM |
| A2AR | (Lenselink et al., 2016a) | 4EIY | Glide | 2.5M | eMolecules (DL) | Ligands | 79 | 2 | 3% (1%) | 73% displ. at 10 µM |
| A2AR MAO-B | (Jaiteh et al., 2018) | 3PWH, 2V61 | DOCK | 0.8M | ZINC (FL) | Multitarget ligands | 13 | 1 | 8% | Ki = 2700 nM (A2AR) IC50 = 5000 nM (MAO-B) |
| 4.6M | ZINC (LL) | 11 | 3 | 27% | Ki = 19 nM (A2AR) IC50 = 100 nM (MAO-B) | |||||
| A2AR | (Ballante et al., 2020) | 4EIY, 3PWH | DOCK | 40K | ZINC (LL, Dark chemical matter) | Selective ligands | 35 | 2 | 6% | Ki = 130 nM |
| A2AR D2R | (Kampen et al., 2021) | 3PWH, homology model | DOCK | 11K | Virtual library (DL) | Multitarget ligands | 10 | 3 | 30% | Ki = 1.2 µM (A2AR) Ki = 0.9 µM (D2R) |
| A2AR | (Tian et al., 2017) | 4EIY, 3PWH | Glide | 2.7M | Chemical supplier: ChemDiv (DL) | Ligands | 63 | 11 | 17% | Ki = 270 nM |
| Adrenergic receptors (adrenoceptors) | ||||||||||
| β2R | (Sabio et al., 2008) | 2RH1 | Glide | 400K | In-house (DL) | Ligands | 56 | 20 (19) | 36% (34%) | Ki = 0.114 nM |
| Glide | 4M | Commercial chemical suppliers (DL) | Ligands | 94 | 11 | 12% | Ki = 13.7 nM | |||
| β2R | (Kolb et al., 2009) | 2RH1 | DOCK | 1M | ZINC (LL) | Ligands | 25 | 6 | 24% | Ki = 9 nM |
| β2R | (Weiss et al., 2013) | 3P0G, 2RH1 | DOCK | 400K | ZINC (FL) | Agonist | 5 | 1 (0) | 20% (0%) | pKi = 3.9 |
| 2.7M | ZINC (LL) | Agonists | 17 | 5 (2) | 29% (12%) | pKi = 7.7 | ||||
| β2R | (Kooistra et al., 2016) | 3P0G | PLANTS+ IFP | 109K | ZINC (FL, cationic) | Agonists | 34 | 18 (15) | 53% (44%) | pEC50 = 7.42 |
| PLANTS | 109K | ZINC (FL, cationic) | Agonists | 28 | 11 | 39% | pEC50 = 6.81 | |||
| PLANTS - IFP score | 109K | ZINC (FL, cationic) | Agonists | 36 | 16 (11) | 44% (31%) | pEC50 = 6.43 | |||
| β2R | (Scharf et al., 2019) | 3SN6, 4LDL, 3NY9, 2RH1 | DOCK | 3.7M | ZINC (LL) | Agonists | 19 | 8 | 42% | pKD = 6.3 |
| β2R | (Chevillard et al., 2019) | 2RH1, 4LDE | FRED | 77K | Virtual library (DL) | Ligands | 127 | 12 (3) | 9% (2%) | KD = 1.01 µM |
| β2R | (Scharf et al., 2020) | 3NY9, 2RH1 | DOCK | 3.7M | ZINC (LL) | Ligands | 27 | 1 | 4% | pKi = 7 |
| Chemokine receptors | ||||||||||
| CXCR4 (CXCR3) | (Schmidt et al., 2015) | 3ODU (homology model) | DOCK | 2.4M | ZINC (LL) | Selective ligands | 6 | 3 | 50% | pKB = 7.18 |
| CXCR4 CXCR3 | 3ODU homology model | DOCK | 2.4M | ZINC (LL) | Multitarget ligands | 4 | 2 | 50% | pKB = 7.30 | |
| CXCR4 | (Mysinger et al., 2012b) | 3ODU | DOCK | 4.2M | ZINC (LL) | Ligands | 23 | 4 (1) | 17% (4%) | Ki = 0.31 µM |
| CXCR4 | (Mishra et al., 2016) | 3ODU | Surflex/ Glide | 13K | Chemical supplier: Chembridge (DL, GPCR focused) | Ligands | 9 | 3 (2) | 33% (22%) | IC50 = 1 µM |
| CXCR4 | (Adlere et al., 2019) | 3ODU | PLANTS | 53K | Selected chemical suppliers (FL, di-cationic) | Ligands | 23 | 4 (1) | 17% (4%) | pIC50 = 5 |
| Dopamine receptors | ||||||||||
| D3R | (Carlsson et al., 2011) | 3PBL | DOCK | 3.6M | ZINC (LL) | Ligands | 25 | 5 | 20% | Ki = 0.3 µM |
| D3R | (Lane et al., 2013) | 3PBL | ICM | 4.1M | Molsoft Screenpub (DL) | Ligands | 25 | 14 | 56% | pKi = 7.12 |
| D3R | 3PBL Dopamine modeled in binding site | ICM | 4.1M | Molsoft Screenpub (DL) | Allosteric ligands | 25 | 8 | 32% | pKi = 6.52 | |
| D3R | (Vass et al., 2014b) | 3PBL | GLIDE | 13K | In-house (FL) | Ligands | 50 | 9 (3) | 18% (6%) | Ki = 0.5 µM |
| D3R | 3PBL MD snapshots | GLIDE | 13K | In-house (FL) | Ligands | 56 | 18 (6) | 32% (11%) | Ki = 0.17 µM | |
| D4R | (Wang et al., 2017) | 5WIU | DOCK | 600K | ZINC (LL, cationic) | Selective ligands | 10 | 2 | 20% | Ki = 0.84 µM |
| D4R | (Lyu et al., 2019) | 5WIU | DOCK | 138M | ZINC (LL) | Ligands (selection by visual inspection) | 124 | 32 | 26% | Ki = 18.4 nM |
| D4R | DOCK | Ligands (selection by docking score only) | 114 | 26 | 23% | Ki = 80 nM | ||||
| D4R | (Ballante et al., 2020) | 5WIU | DOCK | 40K | ZINC (LL, Dark chemical matter) | Selective ligands | 18 | 2 | 11% | Ki = 420 nM |
| Free fatty acid receptors | ||||||||||
| FFA1R | (Lückmann et al., 2019) | 4PHU MD snapshots | Surflex/ ICM | 13M | ZINC (DL) | Allosteric ligands | 99 | 1 | 1% | pEC50 = 5.19 |
| Histamine receptors | ||||||||||
| H1R | (de Graaf et al., 2011) | 3RZE | PLANTS+ IFP score | 109K | ZINC (FL, cationic) | Ligands | 26 | 19 (17) | 73% (65%) | pKi = 8.20 |
| H1R | (Kooistra et al., 2016) | 3RZE | PLANTS: PLANT score | 109K | ZINC (FL, cationic) | Ligands | 33 | 15 (13) | 45% (39%) | pKi = 8.20 |
| PLANTS: IFP score | 109K | 33 | 20 (19) | 61% (58%) | pKi = 7.05 | |||||
| Leukotriene receptors | ||||||||||
| CysLT1R | (Sadybekov et al., 2020) | 6RZ4 | ICM-Pro | 115M | Chemical supplier: Enamine (DL, LL) | Selective ligands | 71 | 5 | 7% | Ki = 0.22 µM |
| CysLT2R | (Sadybekov et al., 2020) | 6RZ6 | ICM-Pro | 115M | Chemical supplier: Enamine (DL, LL) | Selective ligands | 68 | 1 | 1% | Ki = 6.46 µM |
| Melatonin receptors | ||||||||||
| MT1R | (Stein et al., 2020) | 6ME3 | DOCK | 150M | ZINC (LL) | Ligands | 38 | 15 (13) | 39% (34%) | pEC50 = 9 |
| MT1R | (Patel et al., 2020) | 6ME3 | ICM | 8.4M | ZINC (FL) | Ligands | 37 | 4 (0) | 11% (0%) | pKi = 4.58 |
| MT2R | 6ME6 | 39 | 10 | 26% | pKi = 7.63 | |||||
| Muscarinic (acetylcholine) receptors | ||||||||||
| M2R | (Kruse et al., 2013) | 3UON | DOCK | 3.1M | ZINC (FL / LL) | Ligands | 18 | 11 (6) | 61% (33%) | Ki = 390 nM |
| M3R (M2R) | 4DAJ (3UON) | Selective ligands | 16 | 8 (6) | 50% (38%) | Ki = 780 nM | ||||
| M2R | (Fish et al., 2017) | 4MQS | DOCK | 2.2M | ZINC (FL) | Agonists | 10 | 7 (1) | 70% (10%) | Ki = 6.0 µM |
| M2R | (Korczynska et al., 2018) | 3UON | DOCK | 4.6M | ZINC (LL) | Allosteric ligands | 13 | 3 | 23% | pKB = 5.35 |
| Neurotensin receptors | ||||||||||
| NTS1R | (Ranganathan et al., 2017) | 4BUO | DOCK | 0.5M | ZINC (FL) | Ligands | 25 | 8 (0) | 32% (0%) | KD ∼ 0.2–0.3 mM |
| 1.8M | ZINC (LL) | Ligands | 27 | 5 (3) | 19% (11%) | KD = 1.2 µM | ||||
| Opioid receptors | ||||||||||
| KOR | (Negri et al., 2013) | 4DJH | DOCK | 4.5M | ZINC (LL) | Selective ligands | 22 | 4 (0) | 18% (0%) | Ki = 130 µM |
| MOR | (Manglik et al., 2016) | 4DKL | DOCK | 3M | ZINC (LL) | Ligands | 23 | 7 (6) | 30% (26%) | Ki = 2.3 μM |
| KOR | (Zheng et al., 2017) | 4DJH | ICM | 4.5M | Selected chemical suppliers (DL) | Ligands | 43 | 14 | 33% | pKi = 6.82 |
| KOR (MOR) | (Weiss et al., 2018) | 4DJH (4DKL) | DOCK | 3M | ZINC (LL) | Selective ligands | 22 | 9 (6) | 41% (27%) | Ki = 1810 nM |
| Orexin receptors | ||||||||||
| OX2R | (Gunera et al., 2020) | 4S0V | HYBRID, DOCK | 11.3M | ZINC (DL) | Ligands | 43 | 11 (4) | 26% (9%) | pKi = 5.55 |
| OX2R (OX1R) | 4S0V (4ZJ8) | HYBRID, DOCK | 11.3M | ZINC (DL) | Selective ligands | 25 | 6 (1) | 24% (4%) | pKi = 5.80 | |
| Serotonin (5-hydroxytryptamine, 5-HT) receptors | ||||||||||
| 5-HT1BR (5-HT2BR) | (Rodriguez et al., 2014) | 4IAR (4IB4) | DOCK | 1.3M | ZINC (LL, cationic) | Selective ligands | 22 | 11 | 50% | Ki = 0.03 µM |
| 5-HT2BR (5-HT1BR) | (Rataj et al., 2018) | 4IB4, 4NC3 (4IAQ, 4IAR) | Glide | 25K | Mcule (DL, Machine learning) | Selective ligands | 9 | 3 | 33% | Ki = 0.3 nM |
| Smoothened | ||||||||||
| SMO | (Lacroix et al., 2016) | 4JKV | DOCK | 3.2M | ZINC (LL) | Ligands | 21 | 4 (1) | 19% (5%) | IC50 = 5.3 µM |
| SMO | (Lu et al., 2018) | 4JKV, 4QIM | Glide | >1M | Chemical supplier: ChemDiv (DL) | Ligands | 21 | 6 | 29% | IC50 = 47 nM |
↵a Protein Data Bank accession codes for targets and antitargets (in parentheses).
↵b Docking program used and additional scoring functions used, e.g., interaction fingerprints (IFP).
↵c Source of screening library. The type of library is described in parentheses. The libraries were classified into three categories (based on the best match in molecular weight of compounds): DL, drug-like (<500 Da); LL, lead-like (<350 Da); FL, fragment-like (<250 Da). Additional filtering to create target-focused libraries is also described in parentheses.
↵d The presented number of hits and hit rates (number of active compounds/number of experimentally evaluated compounds) is based on the authors’ assessment of the experimental results. Number of hits and hit rates based on a ≤10 µM affinity/activity cutoff are shown in parentheses and are primarily based on binding data (e.g., Ki, KD, KB). If binding data are not available, hit rates were based on functional data (e.g., IC50, EC50). If no parentheses are shown, there were no hits reported with an affinity or activity > 10 µM.
↵e The affinity/activity of the best hit from the virtual screen.
cmpds, compounds; FRED, Fast Rigid Exhaustive Docking; ICM, Internal Coordinate Mechanics; PLANTS, Protein-Ligand ANTSystem.