Role of Ligand-Based Drug Design Methodologies toward the Discovery of New Anti- Alzheimer Agents: Futures Perspectives in Fragment-Based Ligand Design

Abstract

Alzheimer's disease (AD), a degenerative disease affecting the brain, is the single most common source of dementia in adults. The cause and the progression of AD still remains a mystery among medical experts. As a result, a cure has not yet been discovered, even after decade's worth of research that started since 1906, when the disease was first identified. Despite the efforts of the scientific community, several of the biological receptors associated with AD have not been sufficiently studied to date, limiting in turn the design of new and more potent anti-AD agents. Thus, the search for new drug candidates as inhibitors of different targets associated with AD constitutes an essential part towards the discovery of new and more efficient anti-AD therapies. The present work is focused on the role of the Ligand-Based Drug Design (LBDD) methodologies which have been applied for the elucidation of new molecular entities with high inhibitory activity against targets related with AD. Particular emphasis is given also to the current state of fragment-based ligand approaches as alternatives of the Fragment-Based Drug Discovery (FBDD) methodologies. Finally, several guidelines are offered to show how the use of fragment-based descriptors can be determinant for the design of multi-target inhibitors of proteins associated with AD.

Prediction of Multi-Target Networks of Neuroprotective Compounds with Entropy Indices and Synthesis, Assay, and Theoretical Study of New Asymmetric 1,2-Rasagiline Carbamates

“…The model correctly classified more than 90% of active and inactive compounds in the treatment of Alzheimer’s disease on both, training and prediction series. Several guidelines are offered in other paper to show how the use of fragment-based descriptors can be determinant for the design of multi-target inhibitors of proteins associated with Alzheimer’s disease [ 49 ].…”

Medicinal Chemistry Approaches to Neglected Diseases Drug Discovery

“…VS, molecular docking and molecular dynamics (MD) are among some of the most important methods [23,24], where the main goal is to simulate the interaction between small-molecule ligands and biological targets to gather insights into critical intermolecular events [25]. On the other hand, LBDD methods focus on the investigation of known biologically active ligands to produce knowledge that can be applied in multiple ways in the design of new compounds [26,27]. Pharmacophores, quantitative structure-activity relationships (QSAR) and ligandbased VS (LBVS) are strategies usually employed in LBDD studies, both in academia and industry [28][29][30].…”

Fragment-Based Optimization of Small Molecule CXCL12 Inhibitors for Antagonizing the CXCL12/CXCR4 Interaction

“…Targeting a specific ligand may empower regulation, rather than simply elimination, of receptor activity. Futures perspective to the discovery of antagonists for CXCL12/CXCR4 interactions, may include the use of computational methodologies such as Quantitative-Structure Activity Relationships (QSAR) [91-119], especially those focused on the simultaneous classification and prediction of compounds with different biological activities [120-137], including the discovery of inhibitors for proteins associated with one or more diseases [138-143]. Alternatively, complex network theory could be used to gain a better understanding about ligand-protein and protein-protein interactions [143-152].…”