In-silico screening of potential targets from wound healing pathways against Hordenine and selected Bioisostere

Hordenine (4-[2-(Dimethylamino) ethyl] phenol) a plant-based phenethylamine
alkaloid and its shortlisted bioisostere 1-(5-amino-1H-1,2,4-triazol-3-yl)-N-[2-(4-
chlorophenyl) ethyl]-N-methylpiperidin-4-amine, which showed nil-lead likeliness
violation during ADMET screening were docked with eight potential drug targets
from selected wound healing pathways. The results showed that Metalloproteinase9 and Proliferating cell antigen had the lowest binding energy of -6.23 and -6.58
kcal/mol, respectively. However, when considering the molecular interactions were
considered, Tyrosine related protein 1 had the maximum number of interactions with
binding energy of -5.83 kcal/mol and the highest number of hydrogen bonds. The
molecule 1-(5-amino-1H-1,2,4-triazol-3-yl)-N-[2-(4-chlorophenyl)ethyl]-Nmethylpiperidin-4-amine docked well with all the targets and had appreciably lower
binding energies for all the wound healing targets: Casein kinase 1 -14.41Kcal/mol,
Metalloproteinase-9 -11.7241Kcal/mol, Proliferating cell antigen -9.8941Kcal/mol,
Tyrosine related protein 1 -9.4441Kcal/mol, ß2 adrenergic receptors -
8.1941Kcal/mol, Notch1 I D receptor -7.4441Kcal/mol, Dopachrome tautomerase -
6.4 41Kcal/mol and Glycogen synthase kinase 3 beta -5.741Kcal/mol. The
Molecular dynamic simulations of Casein kinase 1 with 1-(5-amino-1H-1,2,4-
triazol-3-yl)-N-[2-(4-chlorophenyl) ethyl]-N-methylpiperidin-4-amine showed that
the Cα Root mean square deviation values were within 1.6 Å throughout the
simulation for the system and the root mean square fluctuations showed that loop
residues (Residues 49 to 57) involved in ligand binding had minimal fluctuations as
compared to the other loop residues. A free binding energy of -10.44 Kcal /mol was
derived from MMPBSA calculations and this corroborated well with the good
binding score obtained by docking. This shows that the protein-ligand complex did
not undergo any major conformational change and was stable throughout the
simulation giving supportive evidence that this molecule could be a promising
candidate for acute and chronic wound healing including diabetic foot ulcers, along
with Hordenine which is an effective inhibitor of hyperpigmentation.