My research target has high sequence homology in humans and model organisms (such as mice/rat), but I am not sure whether the existing small molecule inhibitors can effectively bind and work in cross-species systems.
I want to know whether the conserved domain of the target is sufficient to support cross-species binding of small molecules?
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The cross-species applicability of small molecule compounds is usually based on the conservatism of their mechanism of action, that is, in theory, they can achieve target binding without relying on species differences.
However, it should be noted that different species or cell lines may have significant differences in sensitivity to the same small molecule, which is related to the following factors:
- Target sequence variation: Differences in amino acids in the binding domain can lead to affinity fluctuations (such as single nucleotide polymorphisms affecting ligand binding efficiency);
- Differences in metabolic pathways: Species-specific enzyme systems (such as the cytochrome P450 family) can change the in vivo clearance rate and active metabolite production of small molecules;
- Signal network background: Differences in upstream and downstream regulatory pathways of the same target in different cellular environments may affect the intensity of the biological effect of small molecules.
Therefore, when using across species, experimental verification (such as IC50 determination of cell lines of different species) is required to confirm the sensitivity differences and avoid direct extrapolation of conclusions.
The answer to this question comes from MCE Technical Support.
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