Selective DNA Gyrase Inhibitors: Multi-Target in Silico Profiling with 3D-Pharmacophores

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Drug Discovery

Background:

• DNA gyrase (GyrB) is a crucial target for novel antibiotics.
• ATP-competitive GyrB inhibitors face challenges in clinical development due to off-target activities against human enzymes.
• Early evaluation of selectivity against human ATP-binding enzymes like topoisomerase IIα (TopoII) and Hsp90 is essential.

Purpose of the Study:

• To develop selective 3D-pharmacophore models for GyrB, TopoII, and Hsp90.
• To establish in silico activity profiling for identifying GyrB-selective molecules.
• To provide starting points for hit expansion and lead optimization of novel antibacterial agents.

Main Methods:

• Development of selective 3D-pharmacophore models for GyrB, TopoII, and Hsp90.
• In silico profiling of known GyrB, TopoII, and Hsp90 inhibitors using the developed models.
• In vitro validation of selected compounds for target selectivity.

Main Results:

• GyrB inhibitors 1 and 2 showed no activity against TopoII and Hsp90.
• Potent Hsp90 inhibitors 3 and 4 did not inhibit GyrB or TopoII.
• TopoII inhibitors 5 and 6 were inactive against GyrB and Hsp90.

Conclusions:

• The study demonstrates the utility of target activity profiling using 3D-pharmacophore models.
• This approach facilitates the identification of selective drug candidates.
• It provides a proof of concept for developing selective GyrB inhibitors with reduced off-target effects.