Table 1.
Properties of the cytotoxic payloads studied.
| Payload | Potential H-bond donorsa | Averaged H-bondsb | ΔG flip-flopc (kJ mol−1) | ΔG desorptiond (kJ mol−1) | Bystander effect | AlogPe | Rgf (nm) |
|---|---|---|---|---|---|---|---|
| DXd1 | 3 | 1.3 | 20 ± 5 | 40 ± 5 | Yes | − 0.25 | 0.47 ± 0.02 |
| DXd2 | 5 | 2.3 | 80 ± 5 | 40 ± 5 | No | − 0.15 | 0.49 ± 0.02 |
| MMAE | 4 | 0.7 | 15 ± 5 | 50 ± 5 | Yes | 3.10 | 0.55 ± 0.02 |
| MMAF | 3 | 0.6 | 75 ± 5 | 50 ± 5 | No | 2.70 | 0.56 ± 0.02 |
| DM1 | 2 | 1.3 | 20 ± 5 | 55 ± 5 | Yes | 3.00 | 0.47 ± 0.02 |
| Lys-SMCC-DM1 | 6 | 2.3 | 65 ± 5 | 75 ± 5 | No | 4.00 | 0.62 ± 0.02 |
| DXd1-Linker | 7 | 2.3 | 20 ± 5 | 80 ± 5 | No | 1.05 | 0.75 ± 0.02 |
| SMCC-DM1 | 3 | 1.1 | 25 ± 5 | 75 ± 5 | No | 7.10 | 0.70 ± 0.02 |
aNumber of potential hydrogen bond donors in each payload (based on the functional groups able to donate H-bonds). bAverage number of hydrogen bonds formed between the payload and lipids during the last 1 µs of the MD simulation (distance < 0.35 nm and angle < 30°). cFree energy barrier (in kJ mol⁻1) for the payload to traverse the hydrophobic interior of the lipid bilayer (flip-flop). dFree energy barrier (in kJ mol⁻1) for the payload to desorb from the lipid–water interface into the aqueous phase. eAlogP: Partition coefficient calculated via the ALogP model, indicating relative hydrophobicity. fRadius of gyration (in nm), reflecting the average molecular size of the payload over the MD trajectory.