The Discovery of Putative Small Molecules via Ligand-based Pharmacophore Modelling Targeting Human Tau Protein for an Effective Treatment of Parkinson’s Disease
https://doi.org/10.47836/mjmhs.19.6.12
- Author:
Yahaya Sani Najib
1
,
2
;
Yusuf Oloruntoyin Ayipo
1
,
3
;
Waleed Abdullah Ahmad Alananzeh
1
;
Mustapha Muhammed
4
;
Mohd Nizam Mordi
1
Author Information
1. Centre for Drug Research, Universiti Sains Malaysia, USM 11800, Pulau Pinang, Malaysia&
2. Department of Pharmaceutical and Medicinal Chemistry, Bayero University Kano, PMB 3011, Kano Nigeria
3. Department of Chemistry, Kwara State University, Malete, PMB 1530, Ilorin, Nigeria
4. Department of Clinical and Social administrative Pharmacy Universiti Sains Malaysia, USM 11800, Pulau Pinang, Malaysia
- Publication Type:Journal Article
- Keywords:
Ligand-based modelling;
Human tau protein;
Parkinson’s disease;
aggregation;
virtual screening
- From:Malaysian Journal of Medicine and Health Sciences
2023;19(No.6):83-94
- CountryMalaysia
- Language:English
-
Abstract:
Introduction: The human tau protein is a key protein involved in various neurodegenerative disease (NDs) including
Parkinson’s disease (PD). The protein has high tendency to aggregate into oligomers, subsequently generating insoluble mass in the brain. Symptoms of PD include tremor, bradykinesia, rigidity, and postural instability. Currently drugs
for PD treatment are only symptom-targeted while effective therapeutic treatment remains a challenge. The objective
of this study is to identify novel promising anti-PD drugs using computational techniques. Method: ligand-based
(LB) receptor modelling was conducted using LigandScout, validated and subjected to Glide XP docking, virtual
screening, ADMET, and molecular dynamics predictions. Results: The adopted LB modelling generated pharmacophoric features of 5 hydrogen bond donors, 1 aromatic rings, and 7 hydrogen bond acceptors. The validation result
indicated GH score of 0.73 and EF of 36.30 as validation protocols, probing it to be an ideal model. Using 3D query
of the modelling a total of 192 compounds were retrieved from interbioscreen database containing 70,436 natural
compounds. Interestingly, ligands 1, 2, 3, 4 and 5 orderly indicated higher binding affinities to the receptor with
Glide XP docking of -7.451, -7.368, -7.101, -6.878, and -6.789 compared to a clinical drug Anle138b with -4.552
kcal/mol respectively. Furthermore, molecular dynamics and pkCSM pharmacokinetics demonstrated ligands 1, 2, &
4 having better stability and low toxicity profiles compared to the reference. Conclusion: In summary, the study pave
way for discovery of small molecules that could be recommended as adjuvant /single candidate as ant-PD candidates
upon further translational study.
- Full text:11.2023my1666.pdf
