Research pick: Computers search for Huntington’s disease drug candidates - "Genes to drug: an in-silico approach to design a drug for Huntington disease (HD) in Homo sapiens"

Huntington’s disease, previously known as Huntington’s chorea, is a progressive neurodegenerative disorder. It has a strong genetic component and is considered to be an inherited disease, although one in ten cases is due to an uninherited genetic mutation.

The genetic source of the disease lies in the huntingtin [sic] gene (HTT). We all have two copies of this gene and it codes for the huntingtin protein (Htt). The protein is essential for development and for the body’s nerve cells to function. However, the healthy gene has a repeated section but in Huntington’s disease this repeat is extended beyond a threshold and the resulting proteins are dysfunctional and damage nerve cells giving rise to the symptoms of the disease.

Initially, the condition leads to problems with mood and cognition and progresses to physical disabilities such as involuntary movements and an inability to talk. Ultimately, dementia and increased physical disability, represent the end stages, although the cause of death is often pneumonia triggered by difficulty in clearing fluid from the lungs and aspiration of food.

Symptoms usually begin at between the ages of 20 and 50 and life expectancy depends on age of onset, but is rarely more than 20 years from the time of the appearance of initial symptoms. There are no known cures and those in the later stages of the disease require full-time care.

Writing in the International Journal of Computational Biology and Drug Design, a research team from India, describes a promising new computer-based approach to the development of putative drugs that could one day offer hope a pharmaceutical intervention in Huntington’s disease. Sachin Kumar of the Department of Bioinformatics, Janta Vedic College in Baraut, Baghpat, Uttar Pradesh and colleagues have looked at the two proteins responsible for the symptoms of Huntington’s disease, Mutant Huntingtin protein (HTT) and HTT-interacting protein 1 (HIP-1) as potential targets for a drug-based therapy. They have taken known computer models of these proteins and examined how well a range of small molecule compounds can fit into, or “dock” with, the active site of the proteins. A compound, or “ligand”, that can dock with a protein’s active site can often block the activity of said protein or preclude the entry of the natural molecule that would otherwise trigger an action in the protein if it docks with the active site.

The team has identified four ligands from their in silico experiments with eleven initial candidates. The candidates were chosen as they are modified versions of known pharmaceuticals – tetrabenazine, baclofen, austedo and deutetrabenazine, Haloperidol, and GSK356278. Of the eleven, four were found to dock well with the protein target and so might be tested further as possible drug candidates for Huntington’s disease. The team adds that as our understanding of how mutant HTT causes cellular toxicity in the first place progresses, there is a hope that drug candidates might be modified further to improve the way they might interrupt toxicity.

Kumar, S., Panwar, S., Sharma, M.K. and Sharma, M.K. (2021) ‘Genes to drug: an in-silico approach to design a drug for Huntington disease (HD) in Homo sapiens’, Int. J. Computational Biology and Drug Design, Vol. 14, No. 3, pp.190–201.