Neutron Crystallography May Create Better Drug Designs

Neutron crystallography may lead to new structure-based drug design.

Knowledge gathered from neutron crystallography may be the key to creating more effective, structure-based drug designs.

Neutron crystallography is a complementary technique to X-ray crystallography and can provide details regarding the hydrogen atom and proton positions. Information about H-bonding networks, water molecule orientations, protonation states, and hydrophobic and electrostatic interactions can all be gained through this method, according to a study published by IUCrJ.

The structures that result from neutron crystallography do not suffer radiation damage, since the technique is non-destructive. Past investigators used the technique to explore the drug acetazolamide that binds to human carbonic anhydrase isoform II, which are zinc metalloenzymes that catalyze the interconversion of CO2 and H2O to HCO3-and H+, according to the current study.

This reaction is critical for respiration, fluid secretion, and pH regulation. There are 11 other catalytically-active isoforms besides hCA II, which can cause off-target binding and diminished drug efficacy.

Currently, more than 400 X-ray crystal structures for hCA II have been created, including information about complex inhibitors. However, details about the H-atom positions of the protein and solvent, and the charged state of the bound inhibitor have not been previously known, except for the hCA II/acetazolamide complex, according to the study.

Scientists in the current study examined X-ray and neutron crystallographic structures of hCA II/methazolamide complex. They were able to discover H-bonding and hydrophobic interactions, along with identifying the charged state of methazolamide, according to the study.

Scientists then compared the room-temperature neutron structures of methazolamide and acetazolamide. They observed differences in enthalpic and entropic contributions to drug binding, which scientists said might suggest that hydrophobic forces compensate for the lack of extensive H-bonding network in methazolamide.

An increasing number of neuron structures deposited into the Protein Data Bank led to novel answers that have otherwise been elusive, the study concluded.