Virtual screening and molecular dynamics simulation approach for the identification of potential multi-target directed ligands for the treatment of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a multifactorial neurological disorder characterized by memory loss and cognitive impairment. The currently available single-targeting drugs have miserably failed in the treatment of AD, and multi-target directed ligands (MTDLs) are being explored as an alternative treatment strategy. Cholinesterase and monoamine oxidase enzymes are reported to play a crucial role in the pathology of AD, and multipotent ligands targeting these two enzymes simultaneously are under various phases of design and development. Recent studies have revealed that computational approaches are robust and trusted tools for identifying novel therapeutics. The current research work is focused on the development of potential multi-target directed ligands that simultaneously inhibit acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) enzymes employing a structure-based virtual screening (SBVS) approach. The ASINEX database was screened after applying pan assay interference and drug-likeness filter to identify novel molecules using three docking precision criteria; High Throughput Virtual Screening (HTVS), Standard Precision (SP), and Extra Precision (XP). Additionally, binding free energy calculations, ADME, and molecular dynamic simulations were employed to get structural insights into the mechanism of protein-ligand binding and pharmacokinetic properties. Three lead molecules viz. AOP19078710, BAS00314308 and BDD26909696 were successfully identified with binding scores of −10.565, −10.543 & −8.066 kcal/mol against AChE and −11.019, −12.357 & −10.068 kcal/mol against MAO-B, better score as compared to the standard inhibitors. In the near future, these molecules will be synthesized and evaluated through in vitro and in vivo assays for their inhibition potential against AChE and MAO-B enzymes.

Keywords:

• Alzheimer’s Disease
• multi-target directed ligands
• acetylcholine esterase
• monoamine oxidase
• structure-based virtual screening
• molecular dynamics

Disclosure statement

No potential conflict of interest was reported by the authors.

Acknowledgement

Kailash would like to acknowledge the Indian Council of Medical Research (ICMR), New Delhi, India for awarding Senior Research Fellowship (File No. 45/29/2022-/BIO/BMS). VK is thankful to CSIR New Delhi for providing grant reference number 02/(0354)/19/EMRII. Authors are also thankful to Prof. Raghavendra P. Tiwari, Vice Chancellor of Central University of Punjab, for providing the necessary infrastructure. Dr. Rajnish Kumar is gratefully acknowledged for the access to ‘PARAM Shivay Facility’ under the National Supercomputing Mission, Government of India at the Indian Institute of Technology (BHU), Varanasi.

Additional information

Funding

This work was supported by Indian Council of Medical Research (ICMR), Govt. of India File No. 45/29/2022-/BIO/BMS and Council of Scientific & Industrial Research (CSIR), reference number 02/(0354)/19/EMRII.