De-Novo Ligand Design against Mutated Huntington Gene by Ligand-Based Pharmacophore Modeling Approach.

BACKGROUND: Huntington's disease is characterized by three side effects, including motor disturbances, psychiatric elements, and intellectual weakness. The onset for HD has nonlinear converse associations with the number of repeat sequences of the polyglutamine mutations, so that younger patients have a tendency for longer repeats length. This HD variation is because of a development of a polyglutamine (CAG) repeats in the exon 1 of the Huntingtin protein.

METHODS: In the present study, a few derivatives utilized as a part of the treatment of HD, are used to create the pharmacophore model and based on the features of the pharmacophore model; an attempt is made to design the de-novo drug for the HD protein. HD protein structure was built and docked with the novel ligand, based on shared feature pharmacophore model, through a ligand-based pharmacophore modeling approach.

RESULTS: The novel ligand contains 1 HBAs, 2 HBDs, and 2 aromatic rings. It fulfills all the properties of certain drug-likeness rules, non-toxic in nature. In the docked complex the common interactive amino acids identified are SER 1035, ALA 1062, MET 1068, LEU 1031, and THR 1036, which confirmed the validity and stability of a ligand molecule to be used as a drug in the treatment of Huntington's disease.

CONCLUSION: novel ligand can be used in clinical trials as a drug molecule against the mutations of HD gene and in laboratory procedures for efficacy analysis.