Biochemoinformatics: integrative computational tools at the interface between chemistry and biology

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Anticipating drug side effects by

comparative pharmacology

Chemogenomics Laboratory, Research Program on Biomedical Informatics (GRIB), Institut Municipal d’Investigació

Mèdica and Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain

Drugs having similar side-effect profiles were successfully shown recently to

have also affinity for a common target. Going one step further, this review

highlights the fact that drugs connected by side-effect similarity have also

similar affinity profiles over multiple targets. Given the current low levels of

completeness of drug-target interaction data, one may expect that the number

of common targets for which drug neighbours in a side-effect network have

some level of affinity is likely to increase in the near future. This observation

suggests that preclinical comparative pharmacology, based on in vitro data but

supported strongly by modern in silico methods for drug metabolite prediction

and affinity profiling, represents an attractive strategy to anticipate clinical drug

side effects.

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3. Similar side-effect profiles reveal common targets

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Figure 1. Network of drugs connected by side-effect similarity, with focus on a particular

network path composed of 14 drugs (left). For five drug-pair connections, the probability of

sharing a target higher than 25% and side effect similarity P value below 0.1, as reported in

reference [21], is also shown (values in italics).

Figure 2. The process of transferring the primary target of a drug to its side-effect neighbours in

the network path.

Figure 3. The bioactivity profiles over ten targets of four drugs connected by side-effect

similarity (see Figure 2). The dashed line indicates the activity level of 10 μM. Arrows mark

current missing data for which low micromolar affinity is predicted.

(105)

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(126)

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SERT CHRM1 HRH1 HTR2C ADRA1A NET DAT

(127)

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(129)

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FIGURE 2

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FIGURE 3

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Related subjects : Biology and Chemistry