Computer-aided drug discovery/design methods have played a major role in the development of therapeutically important small molecules for over three decades. These methods are broadly classified as either structure-based or ligand-based methods. Structure-based methods are in principle analogous to high-throughput screening in that both target and ligand structure information is imperative. Structure-based approaches include ligand docking, pharmacophore, and ligand design methods. The article discusses theory behind the most important methods and recent successful applications. Ligand-based methods use only ligand information for predicting activity depending on its similarity/dissimilarity to previously known active ligands. We review widely used ligand-based methods such as ligand-based pharmacophores, molecular descriptors, and quantitative structure-activity relationships. In addition, important tools such as target/ligand data bases, homology modeling, ligand fingerprint methods, etc., necessary for successful implementation of various computer-aided drug discovery/design methods in a drug discovery campaign are discussed. Finally, computational methods for toxicity prediction and optimization for favorable physiologic properties are discussed with successful examples from literature.

/pdf/computational-methods-in-drug-discovery-3sww6kbvd5.pdf

Computational Methods in Drug Discovery

BACE1 (β-secretase, memapsin 2, Asp2) has emerged as a promising target for the treatment of Alzheimer's disease. BACE1 is an aspartic protease which functions in the first step of the pathway leading to the production and deposition of amyloid-β peptide (Aβ). Its gene deletion showed only mild phenotypes. BACE1 inhibition has direct implications in the Alzheimer's disease pathology without largely affecting viability. However, inhibiting BACE1 selectively in vivo has presented many challenges to medicinal chemists. Since its identification in 2000, inhibitors covering many different structural classes have been designed and developed. These inhibitors can be largely classified as either peptidomimetic or non-peptidic inhibitors. Progress in these fields resulted in inhibitors that contain many targeted drug-like characteristics. In this review, we describe structure-based design strategies and evolution of a wide range of BACE1 inhibitors including compounds that have been shown to reduce brain Aβ, rescue the cognitive decline in transgenic AD mice and inhibitor drug candidates that are currently in clinical trials.

/pdf/bace1-b-secretase-inhibitors-for-the-treatment-of-alzheimer-wpl4jm4dt1.pdf

BACE1 (β-Secretase) Inhibitors for the Treatment of Alzheimer's Disease

β-Secretase (memapsin 2; BACE-1) is the first protease in the processing of amyloid precursor protein leading to the production of amyloid-β (Aβ) in the brain. It is believed that high levels of brain Aβ are responsible for the pathogenesis of Alzheimer's disease (AD). Therefore, β-secretase is a major therapeutic target for the development of inhibitor drugs. During the past decade, steady progress has been made in the evolution of β-secretase inhibitors toward better drug properties. Recent inhibitors are potent, selective and have been shown to penetrate the blood-brain barrier to inhibit Aβ levels in the brains of experimental animals. Moreover, continuous administration of a β-secretase inhibitor was shown to rescue age-related cognitive decline in transgenic AD mice. A small number of β-secretase inhibitors have also entered early phase clinical trials. These developments offer some optimism for the clinical development of a disease-modifying drug for AD.

/pdf/developing-b-secretase-inhibitors-for-treatment-of-alzheimer-27645x5062.pdf

Developing β-secretase inhibitors for treatment of Alzheimer’s disease

Background: The guanidine group defines chemical and physicochemical properties of many compounds of medical interest and guanidine-containing derivatives constitute a very important class of therapeutic agents suitable for the treatment of a wide spectrum of diseases. Objective: To review the most important pharmacological properties, mechanisms of action and therapeutic uses of simple guanidine derivatives, cyclic analogues of guanidines as well as peptides, peptidomimetics and peptoids incorporating arginine. Methods: The review presents both the recent patent literature and original papers dealing with guanidine derivatives that show interesting biological activity and emphasizes the newest developing drugs. Conclusion: Recent achievements in the synthesis of guanidine-containing molecules with diverse chemical, biochemical and pharmacological properties make them of great importance to the design and development of novel drugs acting at CNS, anti-inflammatory agents, inhibitors of Na+/H+ exchanger, i...

Biological activities of guanidine compounds.

Docking into multiple receptor conformations ("ensemble docking") has been proposed, and employed, in the hope that it may account for receptor flexibility in virtual screening and thus provide higher enrichments than docking into single rigid receptor structures. The statistical analyses presented in this paper provide quantitative evidence that in some cases docking into a crystallographically derived conformational ensemble does indeed yield better enrichment than docking into any of the individual members of the ensemble. However, these "successful" ensembles account for only a minority of those examined and it would not have been possible to prospectively predict their identity using only protein structural information. A more frequently observed outcome is that the ensemble enrichment is higher than the mean of the enrichments provided by its individual members. An additional and promising finding is that, if a set of known active compounds is available, an approach based on induced-fit docking appears to be a reliable way to construct ensembles which provide relatively high enrichments.

Ensemble Docking into Multiple Crystallographically Derived Protein Structures: An Evaluation Based on the Statistical Analysis of Enrichments

BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Aβ, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC50 = 110 nM).

Acylguanidines as Small-Molecule β-Secretase Inhibitors

Novel pyrrolyl 2-aminopyridines as potent and selective human β-secretase (BACE1) inhibitors

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Acylguanidines as Small-Molecule β-Secretase Inhibitors

Novel pyrrolyl 2-aminopyridines as potent and selective human β-secretase (BACE1) inhibitors