Table 5.
Weighted scoring of compound performance based on in silico and in vitro analysis to facilitate compound selection for in vivo validation.
| Scoring Component | −5 | −1 | 0 | 1 | 2 | 3 | 4 | 5 | Weight |
|---|---|---|---|---|---|---|---|---|---|
| In Silico Analysis of Therapeutic Time Window | |||||||||
| Concordance (acute) | >Top 60% # | Top 50% # | Top 40% # | Top 30% # | Top 20% # | Top 10% # | 10% | ||
| Concordance (chronic) | >Top 60% # | Top 50% # | Top 40% # | Top 30% # | Top 20% # | Top 10% # | 10% | ||
| Pharmacokinetic Properties | |||||||||
| Blood brain barrier penetration | No | Unknown | Yes | 10% | |||||
| Water solubility | Non soluble | Unknown | Soluble | 10% | |||||
| Co-culture Outcome | |||||||||
| Inflammation (TNFa) | >100%& | 100% & | <90% & | <70% & | <50% & | <30% & | <10% & | 15% | |
| Neurotoxicity (NO) | >100%& | 200% & | <90% & | <70% & | <50% & | <30% & | <10% & | 15% | |
| Neuronal viability (MAP2) | <100%& | >115% & | >100% & | >150% & | >200% & | >250% & | >300% & | 20% | |
| Target Engagement (under Inflammatory Conditions) | |||||||||
| Nfe2l2 | ↓ | - | ↑ | 1.25% | |||||
| Gclm | ↓ | - | ↑ | 1.25% | |||||
| Hmox1 | ↓ | - | ↑ | 1.25% | |||||
| Nqo1 | ↓ | - | ↑ | 1.25% | |||||
| Target Engagement (under Non-inflammatory Condition) | |||||||||
| Nfe2l2 | ↓ | - | ↑ | 1.25% | |||||
| Gclm | ↓ | - | ↑ | 1.25% | |||||
| Hmox1 | ↓ | - | ↑ | 1.25% | |||||
| Nqo1 | ↓ | - | ↑ | 1.25% | |||||
The highest achievable score was 4.6 and the lowest −3.6. The higher the score, the more effective the candidate compound. Abbreviations: In silico analysis: #, compounds were arranged according to the absolute value of the iLINCS concordance score. The compounds with a concordance score in the top 10% received 5 points, in the top 10–20%, 4 points, etc.; Co-culture outcome: &, percentage of the effect compared with the non-treated control; MAP2, microtubule-associated protein 2; NO, nitric oxide; TNFα, tumour necrosis factor alpha. Target engagement: ↓, statistically significant downregulation in gene expression compared with the non-treated control; -, no effect on gene expression; ↑, statistically significant upregulation in gene expression compared with the non-treated control.