Pharmacophore-based virtual screening, molecular docking and molecular dynamics simulations study for the identification of LIM kinase-1 inhibitors

Abstract

LIM kinases (LIMKs) are a family of protein kinases involved in the regulation of actin dynamics. There are two isoforms of LIMKs i.e., LIMK1 and LIMK2. LIMK1 is expressed abundantly in neuronal tissues. LIMK1 plays an essential role in the degradation of dendritic spines, which are important for our higher brain functions, such as memory and learning. The inhibition of LIMK1 improves the size and density of dendritic spines and acts as a protective effect against Alzheimer's disease. In this study, we have adopted ligand-based drug design and molecular modelling methods to identify virtual hits. The pharmacophoric features of PF-00477736 were used to screen the Zinc15 compounds library. The identified hits were then passed through drug-likeliness and PAINS filters. Further, comprehensive docking and rigorous molecular dynamics simulation study afforded three virtual hits viz., ZINC504485634, ZINC16940431 and ZINC1091071. The hits showed a better docking score than the standard ligand, PF-00477736. The docking score was found to be –8.85, –7.50 and –7.68 kcal/mol. These hits exhibited optimal binding properties with the target in docking study, blood-brain barrier permeability, in silico pharmacokinetics and low predicted toxicity.

Communicated by Ramaswamy H. Sarma

Keywords:

• LIMK inhibitors
• Alzheimer's disease
• drug discovery
• molecular simulations
• KNIME

Acknowledgement

The authors extend their gratitude toward Professor David A. Case, Department of Chemistry & Chemical Biology, Rutgers University, New Jersey, USA for providing support granting a license for Amber 18. The authors acknowledge the financial support from the Ministry of Education (MoE), New Delhi, India in the form of teaching assistantships to RS, AG and SR.

Disclosure statement

No potential conflict of interest was reported by the author(s).