Identifying Molecular Fragments That Drive 7-Dehydrocholesterol Elevation.

Medications having the unwanted side effect of inhibiting 7-dehydrocholesterol reductase (DHCR7), one of the last enzymes in the cholesterol biosynthesis pathway, account for about 300 million yearly prescriptions in the United States. Many of these drugs are currently prescribed to pregnant women. Many DHCR7-inhibiting medications share chemical similarities, which can be the active substructure responsible for the medication affinity to the enzyme. This work highlights a computational strategy to identify enriched fragments in a set of DHCR7-inhibiting medications. The computational approach used here involves systematic fragmentation of molecules using the molBLOCKS tool, followed by enrichment analysis. The results of this approach highlight putative pharmacophores that might be responsible for the DHCR7-inhibiting activity of some of these medications. The identification of DHCR7-inhibiting substructures is an important step toward knowledge-based drug development and can improve the neurodevelopmental safety of medications.