Changing Paradigm from one Target one Ligand Towards Multi-target Directed Ligand Design for Key Drug Targets of Alzheimer Disease: An Important Role of In Silico Methods in Multi-target Directed Ligands Design

Akhil Kumar, Ashish Tiwari, Ashok Sharma
2018 Current Neuropharmacology  
Alzheimer disease (AD) is now considered as a multifactorial neurodegenerative disorder and rapidly increasing to an alarming situation and causing higher death rate. One target one ligand hypothesis does not provide complete solution of AD due to multifactorial nature of the disease and one target one drug fails to provide better treatment against AD. Moreover, currently available treatments are limited and most of the upcoming treatments under clinical trials are based on modulating single
more » ... get. So, the current AD drug discovery research is shifting towards a new approach for a better solution that simultaneously modulates more than one targets in the neurodegenerative cascade. This can be achieved by network pharmacology, multi-modal therapies, multifaceted, and/or the more recently proposed term "multi-targeted designed drugs". Drug discovery project is a tedious, costly and long-term project. Moreover, multi-target AD drug discovery added extra challenges such as the good binding affinity of ligands for multiple targets, optimal ADME/T properties, no/less off-target side effect and crossing of the blood-brain barrier. These hurdles may be addressed by insilico methods for an efficient solution in less time and cost as computational methods successfully applied to single target drug discovery project. Here, we are summarizing some of the most prominent and computationally explored single targets against AD and further, we discussed a successful example of dual or multiple inhibitors for same targets. Moreover, we focused on ligand and structure-based computational approach to design MTDL against AD. However, it is not an easy task to balance dual activity in a single molecule but computational approach such as virtual screening docking, QSAR, simulation and free energy is useful in future MTDLs drug discovery alone or in combination with a fragment-based method. However, rational and logical implementations of computational drug designing methods are capable of assisting AD drug discovery and play an important role in optimizing multi-target drug discovery. services for people aged ≥65 years will be $236 billion for the year 2016 [3]. Such an alarming data indicates the need to prevent and cure AD and other related dementias in near future. The AD research till now has revealed much about disease pathologies, pathways, and therapeutic drug targets. However, many issues such as biological changes that trigger AD, why it progresses more quickly in some cases than in others and how the disease can be prevented, slowed or stopped completely are still unclear [3] . Recent research in neurodegenerative diseases suggests that AD occurs due to multiple factors such as genetic, environmental and endogenous factors. In this disease, one can observe aggregation of small peptide, protein misfolding, oxidative stress, metal dyshomeostasis, mitochondrial dysfunction, and tau hyperphosphorylation occurring at the same time [4] . The two major hallmark pathologies of AD
doi:10.2174/1570159x16666180315141643 pmid:29542413 pmcid:PMC6080096 fatcat:ylxayop3d5afzboa7eytazyj64