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

Abstract

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 target. 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.

Alzheimer’s Disease Pharmacotherapy in Relation to Cholinergic System Involvement

“…The concept "one molecule-one target-one disease" fails to provide a comprehensive solution for AD treatment due to the complex and multilayered nature of the disease [117]. As a result, nowadays the anti-AD drug research is moving towards a new approach that addresses the various pathways involved in the onset and evolution of this pathology-multi-target-directed ligands (MTDLs) [118]. The novel molecules come with additional challenges such as a fine binding affinity of ligands for multiple targets, favorable pharmacological profile, neuroprotective properties, and drug-like activities, thus suggesting a good BBB permeability [119].…”

Stem cell therapy for Alzheimer's disease

“…We conclude that it is essential to expand our view of pathogenesis beyond Aβ and tau pathology. Current drug design strategies are based on ‘‘one drug-one target’’ paradigm[ 33 ], which until now failed to provide effective treatments against AD, due to the multifactorial nature of the disease[ 34 , 35 ]. Reducing Aβ or tau levels has been the dominant treatment strategy in development to halt, retard, or even reverse the progression of AD pathology.…”

Tick Salivary Compounds for Targeted Immunomodulatory Therapy

“…Multi-target drugs, also known as multifunctional drugs or network therapeutics are more suitable as potential therapeutic solutions in diseases of complex etiology, such as Alzheimer's disease, Parkinson's disease, and neglected tropical diseases (48). Single-target drugs, although highly selective and specific, may not necessarily have better efficacy in these cases (49). Indeed, multi-target drugs tend to be beneficial to face complex disorders, multifactorial health conditions and drug resistance issues (50,51).…”

“…Indeed, multi-target drugs tend to be beneficial to face complex disorders, multifactorial health conditions and drug resistance issues (50,51). Some studies trend to changing paradigm from "one target one ligand" toward "multi-target" as they does not provide a complete solution for multifactorial diseases (49). Therefore, tick salivary compounds with broad-spectrum targets might be useful in these diseases mediated by multiple processes.…”