Computational Investigation of a Series of Small Molecules as Potential Compounds for Lysyl Hydroxylase‑2 (LH2) Inhibition

The catalytic function of lysyl hydroxylase-2 (LH2),
a member of
the Fe­(II)/αKG-dependent oxygenase superfamily, is to catalyze
the hydroxylation of lysine to hydroxylysine in collagen, resulting
in stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs).
Reports show that high amounts of LH2 lead to the accumulation of
HLCCs, causing fibrosis and specific types of cancer metastasis. Some
members of the Fe­(II)/αKG-dependent family have also been reported
to have intramolecular O2 tunnels, which aid in transporting
one of the required cosubstrates into the active site. While LH2 can
be a promising target to combat these diseases, efficacious inhibitors
are still lacking. We have used computational simulations to investigate
a series of 44 small molecules as lead compounds for LH2 inhibition.
Tunneling analyses indicate the existence of several intramolecular
tunnels. The lengths of the calculated O2-transporting
tunnels in holoenzymes are relatively longer than those in the apoenzyme,
suggesting that the ligands may affect the enzyme’s structure
and possibly block (at least partially) the tunnels. The sequence
alignment analysis between LH enzymes from different organisms shows
that all of the amino acid residues with the highest occurrence rate
in the oxygen tunnels are conserved. Our results suggest that the
enolate form of diketone compounds establishes stronger interactions
with the Fe­(II) in the active site. Branching the enolate compounds
with functional groups such as phenyl and pyridinyl enhances the interaction
with various residues around the active site. Our results provide
information about possible leads for further LH2 inhibition design
and development.