Novel and Potential Small Molecule Scaffolds as DYRK1A Inhibitors by Integrated Molecular Docking-Based Virtual Screening and Dynamics Simulation Study

Mir Mohammad Shahroz; Hemant Kumar Sharma; Abdulmalik S A Altamimi; Mubarak A Alamri; Abuzer Ali; Amena Ali; Safar Alqahtani; Ali Altharawi; Alhumaidi B Alabbas; Manal A Alossaimi; Yassine Riadi; Ahmad Firoz; Obaid Afzal

doi:10.3390/molecules27041159

Novel and Potential Small Molecule Scaffolds as DYRK1A Inhibitors by Integrated Molecular Docking-Based Virtual Screening and Dynamics Simulation Study

Molecules. 2022 Feb 9;27(4):1159. doi: 10.3390/molecules27041159.

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, Sri Satya Sai University of Technology and Medical Sciences, Sehore 466001, Madhya Pradesh, India.
² Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al Kharj 11942, Saudi Arabia.
³ Department of Pharmacognosy, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
⁴ Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
⁵ Department of Biological Sciences, Faculty of Science, King Abdulaziz University, P.O. Box 80200, Jeddah 21589, Saudi Arabia.

Abstract

The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a novel, promising and emerging biological target for therapeutic intervention in neurodegenerative diseases, especially in Alzheimer's disease (AD). The molMall database, comprising rare, diverse and unique compounds, was explored for molecular docking-based virtual screening against the DYRK1A protein, in order to find out potential inhibitors. Ligands exhibiting hydrogen bond interactions with key amino acid residues such as Ile165, Lys188 (catalytic), Glu239 (gk+1), Leu241 (gk+3), Ser242, Asn244, and Asp307, of the target protein, were considered potential ligands. Hydrogen bond interactions with Leu241 (gk+3) were considered key determinants for the selection. High scoring structures were also docked by Glide XP docking in the active sites of twelve DYRK1A related protein kinases, viz. DYRK1B, DYRK2, CDK5/p25, CK1, CLK1, CLK3, GSK3β, MAPK2, MAPK10, PIM1, PKA, and PKCα, in order to find selective DYRK1A inhibitors. MM/GBSA binding free energies of selected ligand-protein complexes were also calculated in order to remove false positive hits. Physicochemical and pharmacokinetic properties of the selected six hit ligands were also computed and related with the proposed limits for orally active CNS drugs. The computational toxicity webserver ProTox-II was used to predict the toxicity profile of selected six hits (molmall IDs 9539, 11352, 15938, 19037, 21830 and 21878). The selected six docked ligand-protein systems were exposed to 100 ns molecular dynamics (MD) simulations to validate their mechanism of interactions and stability in the ATP pocket of human DYRK1A kinase. All six ligands were found to be stable in the ATP binding pocket of DYRK1A kinase.

Keywords: DYRK1A; ProTox-II; alzheimer’s disease (AD); kinases; molecular docking; molecular dynamics (MD) simulation; virtual screening.

MeSH terms

Catalytic Domain
Dyrk Kinases
Humans
Molecular Docking Simulation*
Molecular Dynamics Simulation*
Molecular Structure
Protein Kinase Inhibitors* / chemical synthesis
Protein Kinase Inhibitors* / chemistry
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / chemistry*

Substances

Protein Kinase Inhibitors
Protein-Tyrosine Kinases
Protein Serine-Threonine Kinases

Grants and funding

TURSP-2020/124/Taif University