DOI: 10.1002/cmdc.200600314 Ensemble-Docking Approach on BACE-1: Pharmacophore Perception and Guidelines for Drug Design Vittorio Limongelli, [a] Luciana Marinelli,* [a] Sandro Cosconati, [a] Hannes A. Braun, [b] Boris Schmidt, [b] and Ettore Novellino [a] Introduction Alzheimer disease (AD) is a cerebral neurodegenerative pathol- ogy that is characterized by the progressive formation of in- soluble amyloid plaques and fibrillary tangles. [1] Although AD is the most common cause of dementia in western industrialized countries, up to now, there is no approved causal treatment. The available symptomatic treatments or disease modifiers provide only limited benefits to the affected people. The ap- proved drugs, such as vitamin E or AChE inhibitors, slow down but do not stop the disease progression. [2] Thus, a growing need exists for new effective therapies with a specific mode of action which allows control of the onset and the progression of the disease. Over the last decade, much attention has been paid to the cascade of physiological events that contribute or accompany AD. [3–5] It is generally accepted that, the b-amyloid precursor protein (APP) is cleaved by two proteases to gener- ate the 40/42 amino acids long amyloid-b peptides (Ab). The increased Ab formation results in extracellular amyloid plaque deposition and it is accompanied by the intracellular formation of neurofibrillary tangles in the brain. [5,6] The neurotoxicity as- sociated with the Ab oligomerization is thought to cause neu- ronal death, brain inflammation, and finally AD. [7] The APP is processed by the major a- or the minor b-secretase pathway; the latter produces fragments which are further processed by g-secretase. [8] In contrast to the nonpathogenic products of a- secretase, the b-secretase pathway produces pathogenic Ab peptides. After the demonstration that b-secretase (BACE-1), a member of the pepsin family of aspartyl proteases, is the rate- limiting enzyme in the production of Ab [9] and that its genetic depletion in mice abolishes the b-amyloid formation without major side effects, [10] BACE-1 has emerged as a leading target for the therapeutic treatment of Alzheimer disease. [11] Recently, BACE-1 was shown to control the myelination of the peripheral nerves in the late fetal development, the relevance of this find- ing to chronic treatment of adults will have to be consid- ered. [12] To date, several X-ray structures of BACE-1 (hereinafter refer- red to as BACE) have been reported, either in the apo form (PDB codes: 1SGZ and 1W50), in complex with large-size pep- ACHTUNGTRENNUNGtidoACHTUNGTRENNUNGmimetic ligands (1FKN, 1M4H, 1XN2, 1XN3, 1XS7, 2F3E, 1M2, 1M4, 2B8L, 2B8V, and 2FDP), or with rather small inhibi- tors (1W51, 1TQF, and 2G94). An important advance in the elu- cidation of the inhibitor–BACE recognition process has been provided by the 1W51 structure, where the enzyme has been coACHTUNGTRENNUNGcrystallized with the inhibitor 1. [13] Figure 1 highlights the main interactions between 1 and the BACE-1 enzyme. A detailed comparison of the available X-ray structures sug- gests that BACE can assume at least two major conformations mainly differing in the FLAP region, which adopts an open and a closed conformation in the ligand free and ligand bound enzyme, respectively. Thanks to the availability of all these structures, great strides in the development of new BACE in- hibitors have been made by both academic and industrial re- [a] Dr. V. Limongelli, Prof. Dr. L. Marinelli, Dr. S. Cosconati, Prof. Dr. E. Novellino Dipartimento di Chimica Farmaceutica e Tossicologica Università di Napoli “Federico II” Via D. Montesano 49, 80131 Napoli (Italy) Fax:(+ 39)081678139 E-mail:lmarinel@unina.it [b] Dr. H. A. Braun, Prof. Dr. B. Schmidt Clemens Schçpf-Institute of Chemistry and Biochemistry Darmstadt University of Technology Petersenstr. 22, 64287 Darmstadt (Germany) b-Secretase (BACE-1), a key enzyme in the etiopathogenesis and progression of Alzheimer Disease, is the focus of medicinal chemistry efforts both in the pharmaceutical industry and in aca- demia. Despite the availability of diverse peptidomimetic BACE-1 inhibitors, nonpeptidic compounds suitable for oral delivery and transport across the blood brain barrier are in great demand. Herein, a number of active and structurally diverse inhibitors were selected and subjected to an ensemble-docking process into five BACE-1 X-ray structures. The calculated bioactive conforma- tions of these inhibitors allowed us to build an exhaustive phar- macophore model, which captures both the common geometric and electronic features essential for enzyme inhibition. The model is intended to aid the rational design of new BACE-1 inhibitors. Furthermore, a comparison of BACE/cathepsin D X-ray structures was made to provide guidelines for the design of BACE-selective inhibitors. ChemMedChem 2007,2,1–13 # 2007 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim 1 These are not the final page numbers! ÞÞ