Rational polypharmacology drug design AND Optimization of drug safety profile
SPILLO-PBSS can be used for polypharmacology according to various possible strategies, depending on the problem to be solved.
As an example, let’s assume you have a compound of which the pharmacological activity is known, but the target(s) to which such effect is due is/are still unknown, and nothing is known about its safety profile. Let’s assume your aim is to develop a multi-target drug (MTD) with a good safety profile.
By using SPILLO-PBSS we are able to screen and rank the whole available human structural proteome and to provide a list of the potential target and off-target proteins of the considered compound, along with many structural details concerning the potential binding sites (PBSs) on the identified proteins. Then, by analyzing the top-ranked proteins and their relative ranking positions it is possible:
> to identify the main target responsible for the known (positive) biological effect of the compound
> to recognize secondary targets belonging to the same network of the considered disease
> to identify secondary targets potentially responsible for adverse effects of the compound
Moreover, the position and orientation of the compound in its binding sites within the 3D-structures of the various targets are also provided by the calculation, along with the relative importance of the amino acids of the binding sites in stabilizing the interaction with the compound. Then, the roles of the various targets and the biomolecular mechanisms in which they are involved can be clarified.
On this bases it is possible, for example, to rationally modify the original compound (or to rationally generate a set of derivatives) with the aim of increasing the affinity for the secondary targets involved in the condition you want to treat, and with the aim of decreasing the affinity for the secondary targets responsible for undesired effects, while preserving the affinity for the main target. Then, the goodness of the new compound(s) can be evaluated by performing further in silico screening(s) and by comparing old and new ranking positions of the various targets.
This procedure can be repeated until the best compromise between the aspects described above is found.
Note 1 - Advantages over traditional structure-based approaches. Unlike traditional structure-based approaches, SPILLO-PBSS is purposely designed to be successful in identifying target proteins of any small molecule through a direct identification of its binding sites within protein 3D-structures, even when their conformations (e.g., experimentally obtained in the absence of the small molecule of interest) are strongly distorted and not suitable for the binding. This unique feature allows SPILLO-PBSS to identify target and off-target proteins not detectable by traditional approaches. See 'Comparison with other tools' >>
Note 2 - Optimization of animal testing. An even more in-depth search for targets and off-targets can also be carried out by screening and ranking protein databases of organisms other than Homo sapiens (e.g., Mus musculus, Rattus norvegicus). Then, cross-species transferability analyses (e.g., from Homo sapiens to Rattus norvegicus, or vice versa) can be carried out, aimed at evaluating the reliability of animal models and optimizing animal testing. Between-species differences in drug response could also be explained at biomolecular level.
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Comparison with traditional structure-based approaches
Identifying target proteins responsible for toxic effects of xenobiotics
Main applications of SPILLO-PBSS to the drug R&D process
A short description of SPILLO-PBSS
Experimental validation published in peer-reviewed scientific journal