▪ Abstract Degenerative diseases of the brain were long considered among the most obscure and intractable of human maladies. However, recent advances in understanding their mechanisms have brought us to the verge of potential disease-modifying agents. This progress is perhaps best exemplified by the case of Alzheimer's disease. The application of molecular pathology and genetics has led to the recognition that the four genes implicated to date in familial Alzheimer's disease all chronically elevate cerebral levels of the amyloid β-protein (Aβ). Accordingly, small molecule inhibitors of the β- and γ-secretases, the proteases that generate Aβ from its precursor, are under active development, and some have shown in vivo efficacy in mouse models. An alternative approach, active or passive immunization against Aβ, has received extensive pre-clinical validation in mice, but an effective preparation free of significant side effects in humans is still awaited. Several other potential therapies are also reviewed h...

Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics.

Molecular docking methods are commonly used for predicting binding modes and energies of ligands to proteins. For accurate complex geometry and binding energy estimation, an appropriate method for calculating partial charges is essential. AutoDockTools software, the interface for preparing input files for one of the most widely used docking programs AutoDock 4, utilizes the Gasteiger partial charge calculation method for both protein and ligand charge calculation. However, it has already been shown that more accurate partial charge calculation - and as a consequence, more accurate docking- can be achieved by using quantum chemical methods. For docking calculations quantum chemical partial charge calculation as a routine was only used for ligands so far. The newly developed Mozyme function of MOPAC2009 allows fast partial charge calculation of proteins by quantum mechanical semi-empirical methods. Thus, in the current study, the effect of semi-empirical quantum-mechanical partial charge calculation on docking accuracy could be investigated. The docking accuracy of AutoDock 4 using the original AutoDock scoring function was investigated on a set of 53 protein ligand complexes using Gasteiger and PM6 partial charge calculation methods. This has enabled us to compare the effect of the partial charge calculation method on docking accuracy utilizing AutoDock 4 software. Our results showed that the docking accuracy in regard to complex geometry (docking result defined as accurate when the RMSD of the first rank docking result complex is within 2 A of the experimentally determined X-ray structure) significantly increased when partial charges of the ligands and proteins were calculated with the semi-empirical PM6 method. Out of the 53 complexes analyzed in the course of our study, the geometry of 42 complexes were accurately calculated using PM6 partial charges, while the use of Gasteiger charges resulted in only 28 accurate geometries. The binding affinity estimation was not influenced by the partial charge calculation method - for more accurate binding affinity prediction development of a new scoring function for AutoDock is needed. Our results demonstrate that the accuracy of determination of complex geometry using AutoDock 4 for docking calculation greatly increases with the use of quantum chemical partial charge calculation on both the ligands and proteins.

/pdf/application-of-the-pm6-semi-empirical-method-to-modeling-4d9kunvepw.pdf

Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock

The carbamate group is a key structural motif in many approved drugs and prodrugs. There is an increasing use of carbamates in medicinal chemistry and many derivatives are specifically designed to make drug–target interactions through their carbamate moiety. In this Perspective, we present properties and stabilities of carbamates, reagents and chemical methodologies for the synthesis of carbamates, and recent applications of carbamates in drug design and medicinal chemistry.

Organic carbamates in drug design and medicinal chemistry.

β-Lactams: Versatile Building Blocks for the Stereoselective Synthesis of Non-β-Lactam Products

Over the past fifty years, hundreds of polyyne compounds have been isolated from nature. These often unstable molecules are found in sources as common as garden vegetables and as obscure as bacterial cultures. Naturally occurring polyynes feature a wide range of structural diversity and display an equally broad array of biological properties. Early synthetic efforts relied primarily on Cu-catalyzed, oxidative acetylenic homo- and heterocoupling reactions to assemble the polyyne framework. The past 25 years, however, have witnessed a renaissance in the field of polyyne natural product synthesis: transition-metal-catalyzed alkynylation reactions and asymmetric transformations have combined to substantially expand access to natural polyynes. This Review recounts these synthetic achievements and also highlights both the natural source(s) and biological relevance for many of these compounds.

Synthesis of Naturally Occurring Polyynes

The treatment of HIV and AIDS was revolutionized by the introduction of peptidomimetic aspartyl protease inhibitors. One of the major limitations of this type of therapy is that higher therapeutic doses are necessary because of the presence of 'peptide-like' features in the drugs. Therefore, adequate supplies and cost effective syntheses of these drugs are of utmost importance. To date, there are six protease inhibitors approved by the United States Food and Drug Administration (FDA) for the treatment of HIV and AIDS. This review focuses on the published syntheses of currently FDA approved HIV protease inhibitor drugs, their isosteres and ligands.

/pdf/syntheses-of-fda-approved-hiv-protease-inhibitors-4rtehv90jm.pdf

Syntheses of FDA Approved HIV Protease Inhibitors.

Structure-based design and synthesis of a number of potent and selective memapsin 2 inhibitors are described. These inhibitors were designed based upon the X-ray structure of memapsin 2-bound inhibitor 3 that incorporates methylsulfonyl alanine as the P2-ligand and a substituted pyrazole as the P3-ligand. Of particular importance, we examined the ability of the substituted isophthalic acid amide derivative to mimic the key interactions in the S2-S3 regions of the enzyme active sites of 3-bound memapsin 2. We investigated various substituted phenylethyl, alpha-methylbenzyl, and oxazolylmethyl groups as the P3-ligands. A number of inhibitors exhibited very potent inhibitory activity against mempasin 2 and good selectivity against memapsin 1. Inhibitor 5d has shown low nanomolar enzyme inhibitory potency (Ki=1.1 nM) and very good cellular inhibitory activity (IC50=39 nM). Furthermore, in a preliminary study, inhibitor 5d has shown 30% reduction of Abeta40 production in transgenic mice after a single intraperitoneal administration (8 mg/kg). A protein-ligand X-ray crystal structure of 5d-bound memapsin 2 provided vital molecular insight that can serve as an important guide to further design of novel inhibitors.

Design, synthesis, and X-ray structure of potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands.

A review on the syntheses of bioactive compounds published since 1995 using tartaric acid and its derivatives as synthons is presented.

/pdf/tartaric-acid-and-tartrates-in-the-synthesis-of-bioactive-1vsc059zd8.pdf

Tartaric Acid and Tartrates in the Synthesis of Bioactive Molecules

A stereoselective synthesis of (+)-boronolide.

A stereoselective synthesis of (+)-boronolide is described. The key steps involve a stereoselective reduction of an α-hydroxy ketone, allylation of an α-hydroxy aldehyde and a ring-closing olefin metathesis of a homoallylic alcohol derived acrylate ester utilizing Grubbs' catalyst.

A Stereoselective Synthesis of (+)-Boronolide.

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