Table 1. Summary of the LDM benchmark outcomes.
The results are organised by scenario: self refinement, chemotype switch and pharmacology switch. Each line describes an LDM experiment including the origin and destination X-ray structures as well as the overall VS performance outcome. The best LDM model is compared to the origin X-ray structure in recovery of known ligands vs. decoys, selectivity of agonists over inhibitors (or vice-versa) and chemotype enrichment. VS recovery and selectivity performance is improved ↑, similar → or worse ↓ using NSQ_AUC values. VS chemotype enrichment evaluates the LDM refinement ligand chemotype enrichment by comparing the EF1 values of LDM models with their origin X-ray structure. It is “improved” when an LDM model outperforms the origin X-ray structure, and it is “narrowed” when the same performance is observed and EF1 value for other chemotypes is worse for the LDM model. LDM experiments were assigned to two groups based on the similarity of their LDM model binding pose to that of the destination X-ray structure and their improvement in VS performance over the origin X-ray structure. Group A includes LDM models with similar binding poses and improved performance and group B includes LDM models with a different binding pose and improved performance or a similar binding pose and no performance improvement. CCR5 agonist ligands were not available from the GLL/GDD, hence VS selectivity for the self refinement CCR5-MRV experiment was not calculated and is marked N/A.
| LDM benchmark scenarios | GPCR | Origin X-ray | Destination X-ray | Group | VS recovery | VS selectivity | VS chemotype enrichment | Figure |
|---|---|---|---|---|---|---|---|---|
| Self refinement | B2AR | 4LDE-BI (ago.) | - | A | ↑ | ↑ | improved | Fig 3 |
| B2AR | 3P0G-BI (ago.) | - | A | ↑ | ↑ | improved | S5 Fig | |
| AA2AR | 4EIY-ZM (inhib.) | - | A | → | ↑ | narrowed | S6 Fig | |
| AA2AR | 3PWH-ZM (inhib.) | - | A | → | ↓ | narrowed | S7 Fig | |
| M2R | 3UON-QNB (inhib.) | - | A | → | ↑ | narrowed | S8 Fig | |
| M2R | 4MQS-IXO (ago.) | - | A | ↑ | ↑ | narrowed | S9 Fig | |
| H1R | 3RZE-DOX (inhib.) | - | A | → | ↑ | improved | S10 Fig | |
| 5-HT1B | 4IAR-ERG (inhib.) | - | A | ↓ | ↑ | narrowed | S11 Fig | |
| B2AR | 2RH1-CAR (inhib.) | - | B | ↓ | ↓ | improved | Fig 4 | |
| AA2AR | 2YDV-NEC (ago.) | - | B | ↓ | ↓ | narrowed | S12 Fig | |
| CCR5 | 4MBS-MRV (inhib.) | - | B | → | N/A | narrowed | S13 Fig | |
| DOR | 4N6H-NAL (inhib.) | - | B | ↑ | ↑ | improved | S14 Fig | |
| Chemotype switch | B2AR | 4LDO-ADR (ago.) | 4LDL-ISO (ago.) | A | ↑ | ↑ | improved | Fig 5 |
| B2AR | 3NY9-KOL (inhib.) | 2RH1-CAR (inhib.) | A | ↑ | ↑ | improved | S15 Fig | |
| AA2AR | 3QAK-UK (ago.) | 2YDV-NEC (ago.) | A | ↑ | ↑ | improved | S16 Fig | |
| B2AR | 3D4S-TIM (inhib.) | 3NY8-ICI (inhib.) | A | ↓ | ↑ | narrowed | S17 and S18 Figs | |
| AA2AR | 3PWH-ZM (inhib.) | 3RFM-CAF (inhib.) | B | ↑ | ↑ | improved | Fig 6 | |
| AA2AR | 3UZA-T4G (inhib.) | 3REY-XAC (inhib.) | B | ↑ | ↑ | improved | S19 Fig | |
| Pharmacology switch | B2AR | 2RH1-CAR (inhib.) | 4LDE-BI (ago.) | A | ↑ | ↑ | improved | Fig 7 |
| M2R | 3UON-QNB (inhib.) | 4MQS-IXO (ago.) | A | ↑ | ↑ | improved | S20 Fig | |
| M2R | 4MQS-IXO (ago.) | 3UON-QNB (inhib.) | A | ↑ | ↑ | improved | S21 Fig | |
| B2AR | 3P0G-BI (ago.) | 2RH1-CAR (inhib.) | B | ↑ | ↑ | improved | Fig 8 | |
| AA2AR | 3EML-ZM (inhib.) | 2YDV-NEC (ago.) | B | ↑ | ↑ | narrowed | S22 Fig | |
| AA2AR | 3QAK-UK (ago.) | 3EML-ZM (inhib.) | B | ↑ | ↑ | improved | S23 Fig |