The Search for Drug Leads Targeted to the β -Secretase: An Example of the Roles of Computer Assisted Approaches in Drug Discovery

Abstract

The inhibition of beta-secretase has become a very promising approach to control the onset and progression of Alzheimer's disease due to its involvement in the generation of amyloid plaques. The main goal of the many drug discovery projects targeting this enzyme is the identification of highly specific, non-peptidic compounds with low molecular weight, characteristics that are desirable for drug leads with low toxicity that have to transverse the blood brain barrier. We describe the main approaches used in the discovery of novel inhibitors, including substrate specificity, target structure based design, and high throughput screening (HTS), both in vitro and in silico. We place special emphasis in the receptor based design and in silico HTS, two strategies that make wide use of computer assisted tools. To exemplify the usefulness and versatility of computer tools in this endeavor we use the computer generated 'enzyme's binding site cast' to rationalize qualitatively some salient structural features of known beta-secretase second generation inhibitors, and for guiding the review of many of the ligands whose complexes with the enzyme have been studied by X-ray crystallography. We discuss the use made by other authors of molecular modelling for the understanding of the very special characteristics of ligand binding to beta-secretase and for the design of new inhibitors. Finally, we review the quest for non-peptidic inhibitors that has led to the use of HTS in vitro and in silico. The screening of extensive libraries resulted in a few low affinity compounds that do not fit into the key S1/S1' pockets, indicating that this is not an easy target to block.

Bis(7)‐tacrine Derivatives as Multitarget‐Directed Ligands: Focus on Anticholinesterase and Antiamyloid Activities

“…With this concept in mind, we decided to modify the structure of 1 by replacing the heptamethylene chain with more rigid aromatic spacers, such as in compounds 2 – 4 (Figure 1). In principle, this modification might have positive consequences on the profile of the new hybrids: 1) a tighter binding at AChE through possible additional π–π interactions with several aromatic residues present in the enzyme gorge; 2) a planar aromatic surface available for protein–protein interactions;21 3) a higher molecular hindrance to better address the extended substrate binding site requirements of BACE‐1 22. On the basis of this rationale, derivatives 2 – 4 should possess a better inhibition profile against AChE and, more importantly, against amyloid formation and aggregation.…”

Strategies for Inhibiting Protein Aggregation: Therapeutic Approaches to Protein-Aggregation Diseases

“…Because BACE-1 is a potentially attractive therapeutic target, extensive screens for small-molecule inhibitors were conducted both in silico and in vitro, but these yielded only low-affi nity compounds, suggesting that this is a diffi cult enzyme to target (Villaverde et al 2007;Hunt and Turner 2009 ) . In this respect, it shares this unfortunate property with other aspartyl proteases, which have an extended substrate-binding site (Hong et al 2000;Vassar 2001 ) .…”

On a Possible Neutral Charge State for the Catalytic Dyad in β-Secretase When Bound to Hydroxyethylene Transition State Analogue Inhibitors

“…1 The genesis of this construct is catalyzed by a tandem of two proteases identified as β-and γ-secretases. 1,2 It is known that the former enzyme (also referred to as BACE-1 and Memapsin 2) participates in the rate-limiting step of the hydrolytic process that leads to the APP fragments, 1À3 a fact that has converted β-secretase into a major target for drugs against Alzheimer's disease. 2,4,5 There are several issues related to the computer-aided design of novel ligands that could enhance the success of in silico high throughput screening protocols but that have not been fully addressed yet.…”

“…1,2 It is known that the former enzyme (also referred to as BACE-1 and Memapsin 2) participates in the rate-limiting step of the hydrolytic process that leads to the APP fragments, 1À3 a fact that has converted β-secretase into a major target for drugs against Alzheimer's disease. 2,4,5 There are several issues related to the computer-aided design of novel ligands that could enhance the success of in silico high throughput screening protocols but that have not been fully addressed yet. One of the most vital ones is the protonation state of the many buried acidic residues found in this protein, including the active site Asp dyad, which lends to this enzyme an optimal catalytic activity at low pH.…”