Designing lysyl hydroxylase inhibitors for oral submucous fibrosis - Insights from molecular dynamics.

Alpha-ketoglutarate (αKG) dependent Lysyl hydroxylase (LH) is a critical enzyme in the post-translational conversion of lysine into hydroxylysine in collagen triple helix and telopeptide regions. Overexpression of LH increases collagen hydroxylation and covalent cross-linkage, causing fibrosis. Currently, no drugs are available to inhibit LH potentially. Virtual screening of the Zinc database was employed to identify new leads. They were docked using Glide. Lead1 complex exhibits a notably superior docking score compared to other leads. This complex hinders iron stabilization by engaging with the HXD..Xn..H motif and competitively inhibiting 2OG binding at the catalytic site via interactions with Cys691 and Arg729 by forming a salt bridge. Molecular dynamics simulations over a 500 ns time scale and molecular mechanics Poisson-Boltzmann surface area calculations illustrate the stable binding of Leads. DCCA analysis finds the coordinated residue motions and the influence of the second coordinating sphere in long-range interactions. In-silico results were validated by quantifying the amount of collagen in zebrafish through histology and hydroxyproline assay. These findings demonstrated a reduction in collagen deposition in the treated samples compared to the positive control. This computational study unveiled insights into how leads may impede collagen lysine hydroxylation and potentially impact collagen-related processes.