Repurposing Drugs for Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron protein SMN. The SMN locus on chromosome 5q13 contains two inverted copies of SMN called SMN1 and SMN2 which are 99% identical at the amino acid level. SMN1is a fully functional protein and SMN2 skips axon 7 90% of the time. Skipping of exon 7 produces non-functional protein product. 10% of the SMN2 protein includes exon 7 and is fully functional. In the SMA disease state, mutations in the SMN1 locus are the cause of the disease state. Because only 10% of SMN2 is of the fully functional form, it is not sufficient to overcome the deficiency produced by the loss of the SMN1 product. A therapy that either increase the amount of SMN2 product made or to increase the inclusion of exon 7 has been proposed for the treatment of SMA.
For this reason, strategies that enhance SMN2 splice variant expression that yields active SMN protein have been considered of therapeutic interest. In this section we will use the SMN2 enhancing experiments stored in the ChEMBL DB to validate a predictive model that allows prediction of SMN2 enhancing activity for the 1.5M unique molecules with 13M activity records in te DB focusing on molecules that are actually prescription drugs.
About 3k among the 1.5M annotated molecules are prescription drugs. For some of them, there is a record of activity on SMN2 expression experiments, but for the most that don’t have any, there is a predicted score. The variable ActualPluspredictedSMN2Score contains the actual score if it exists, but the predicted one if it doesn’t. These scores have a -log(molar potency) scale.
Applying the dashboard based selection methods described in the prediction of SMN2 activity section upon prescription drugs we have created unique drug target pairs with average scores per pair: the already described ActualPluspredictedSMN2Score and the chemblActivityScoreC which shows the effect that the molecule average score for each particular target.
The graph below shows ActualPluspredictedSMN2Score vs chemblActivityScoreC . Marked dots are displayed on the right side showing the targets where the drugs have an activity record and the value, in bars of their potency at target compared to the potency enhancing SMN2 expression.
It could be interesting checking what they do in animal models…
A different view showing the number of records instead of target chemblActivityScoreC for chemblActivityScoreC >5. Here we can estimate the confidence by the number of repeats…
And finally a treemap of the repurposed drugs for SMA showing the clinical phase achieved, current indications, published MoAs and colored by their potency enhancing SMN2 expression.
Below, the table with the results.