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‘Drug‐likeness’, a qualitative property of chemicals assigned by experts committee vote, is widely integrated into the early stages of lead and drug discovery. Its conceptual evolution paralleled work related to Pfizer's ‘rule of five’ and lead‐likeness, and is placed within this framework. The discrimination between ‘drugs’ (represented by a collection of pharmaceutically relevant small molecules, some of which are marketed drugs) and ‘nondrugs’ (typically, chemical reagents) is possible using a wide variety of statistical tools and chemical descriptor systems. Here we summarize 18 papers focused on drug‐likeness, and provide a comprehensive overview of progress in the field. Tools that estimate drug‐likeness are valuable in the early stages of lead discovery, and can be used to filter out compounds with undesirable properties from screening libraries and to prioritize hits from primary screens. As the goal is, most often, to develop orally available drugs, it is also useful to optimize drug‐like pharmacokinetic properties. We examine tools that evaluate drug‐likeness and some of their shortcomings, challenges facing these tools, and address the following issues: What is the definition of drug‐likeness and how can it be utilized to reduce attrition rate in drug discovery? How difficult is it to distinguish drugs from nondrugs? Are nondrug datasets reliable? Can we estimate oral drug‐likeness? We discuss a drug‐like filter and recent advances in the prediction of oral drug‐likeness. The heuristic aspect of drug‐likeness is also addressed. © 2011 John Wiley & Sons, Ltd. WIREs Comput Mol Sci 2011 1 760–781 DOI: 10.1002/wcms.52 This article is categorized under: Computer and Information Science > Chemoinformatics

Remote loading of liposomes by trans-membrane gradients is used to achieve therapeutically efficacious intra-liposome concentrations of drugs. We have developed Quantitative Structure Property Relationship (QSPR) models of remote liposome loading for a dataset including 60 drugs studied in 366 loading experiments internally or elsewhere. Both experimental conditions and computed chemical descriptors were employed as independent variables to predict the initial drug/lipid ratio (D/L) required to achieve high loading efficiency. Both binary (to distinguish high vs. low initial D/L) and continuous (to predict real D/L values) models were generated using advanced machine learning approaches and five-fold external validation. The external prediction accuracy for binary models was as high as 91–96%; for continuous models the mean coefficient R2 for regression between predicted versus observed values was 0.76–0.79. We conclude that QSPR models can be used to identify candidate drugs expected to have high remote loading capacity while simultaneously optimizing the design of formulation experiments.

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Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis by generating α-1,6-glucosidic branches from α-1,4-linked glucose chains, to increase solubility of the glycogen polymer. Mutations in the GBE1 gene lead to the heterogeneous early-onset glycogen storage disorder type IV (GSDIV) or the late-onset adult polyglucosan body disease (APBD). To better understand this essential enzyme, we crystallized human GBE1 in the apo form, and in complex with a tetra- or hepta-saccharide. The GBE1 structure reveals a conserved amylase core that houses the active centre for the branching reaction and harbours almost all GSDIV and APBD mutations. A non-catalytic binding cleft, proximal to the site of the common APBD mutation p.Y329S, was found to bind the tetra- and hepta-saccharides and may represent a higher-affinity site employed to anchor the complex glycogen substrate for the branching reaction. Expression of recombinant GBE1-p.Y329S resulted in drastically reduced protein yield and solubility compared with wild type, suggesting this disease allele causes protein misfolding and may be amenable to small molecule stabilization. To explore this, we generated a structural model of GBE1-p.Y329S and designed peptides ab initio to stabilize the mutation. As proof-of-principle, we evaluated treatment of one tetra-peptide, Leu-Thr-Lys-Glu, in APBD patient cells. We demonstrate intracellular transport of this peptide, its binding and stabilization of GBE1-p.Y329S, and 2-fold increased mutant enzymatic activity compared with untreated patient cells. Together, our data provide the rationale and starting point for the screening of small molecule chaperones, which could become novel therapies for this disease.

The problem of global optimization is pivotal in a variety of scientific fields. Here, we present a robust stochastic search method that is able to find the global minimum for a given cost function, as well as, in most cases, any number of best solutions for very large combinatorial ''explosive'' systems. The algorithm iteratively eliminates variable values that contribute consistently to the highest end of a cost function's spectrum of values for the full system. Values that have not been eliminated are retained for a full, exhaustive search, allowing the creation of an ordered population of best solutions, which includes the global minimum. We demonstrate the ability of the algorithm to explore the conformational space of side chains in eight proteins, with 54 to 263 residues, to reproduce a population of their low energy conformations. The 1,000 lowest energy solutions are identical in the stochastic (with two different seed numbers) and full, exhaustive searches for six of eight proteins. The others retain the lowest 141 and 213 (of 1,000) conformations, depending on the seed number, and the maximal difference between stochastic and exhaustive is only about 0.15 Kcal͞mol. The energy gap between the lowest and highest of the 1,000 low-energy conformers in eight proteins is between 0.55 and 3.64 Kcal͞mol. This algorithm offers real opportunities for solving problems of high complexity in structural biology and in other fields of science and technology.M any problems in life sciences and in other fields of science and technology are of high complexity, thus requiring sophisticated methods of searching and scoring to achieve the ability to study and to simulate them by means of a computer simulation. An excellent search method coupled with a highly reliable scoring method should allow comparisons to some natural phenomena. In this article, we have taken the approach of comparing best populations found by a stochastic search method to a full, exhaustive search, as the crucial test of this method. However, comparisons to experimental results also are included. The problem chosen to exemplify this method is the positions of side chains in proteins, which is essential for both theoretical and experimental purposes. On the theoretical side, it is a subproblem in de novo protein structure prediction. It is essential for structure-based drug design (1), for inverse folding and threading algorithms (2), for predicting the effect of mutations on structure (3), for ab initio predictions of tertiary structure (4), for homology-based modeling (5), and others. From the x-ray crystallographer's point of view, it could speed the placement of side chains using the electron density maps of the main chain before refinement calculations. The main limitation is the large amount of possible conformations that each side chain may adopt (6). An exhaustive search of all possible conformations is beyond the scope of state of the art computers.Current strategies for side chain addition to a given backbone differ in three categories. The ...

Acylphosphonic acids ( 5 ) and methyl hydrogen acylphosphonates (3) were synthesized by di-and mono-demethylation of dimethyl acylphosphonates (I ). Spectroscopic data (i.r., 31P and 'H n.m.r.) are reported for these types of compounds for the first time. Examination of their hydrolytic stability under acidic and basic conditions revealed that except for methyl hydrogen acylphosphonates (3) that are unstable under highly alkaline pH conditions, the C-P bond in these types of compounds is stable in most cases. Nucleophilic reagents, e.g. amines, borohydride, or hydroxylamine react with the carbonyl group of ionized acylphosphonates with the preservation of the C-P bond, to yield or-imino-, a-hydroxy-, or or-oxyimino-alkylphosphononate anions, respectively. Semi-empirical quantum mechanical (MNDO/H) calculations were performed on benzoylphosphonic acid (5c) and on the esters and anions derived from it, as representatives of their classes, in order to assess bond lengths and preferred conformations, and to estimate charges on the carbonyl and phosphoryt groups. Calculations show that for both neutral and ionized (anions) compounds free rotation around the C-P bond is expected due to the low energy barriers.Phosphonic acid analogues of naturally occurring phosphates or of carboxylic acids have attracted considerable interest as potential regulators, mediators, or inhibitors of metabolic processes.'.* In the large group of compounds prepared and studied, there is an abundance of analogues of lipids, sugar phosphates, nucleotides, or amino acids,2 etc., containing C-P bonds in a variety of structures. However, the compounds hitherto studied belong almost entirely to the class of alkylphosphonates with only a handful of examples of acylphosphonates among them.3 The few instances of reported acylphosphonic acids or monoesters have been prepared, characterized, and used as salts, mostly for studying their biochemical properties. The free alkyl hydrogen acylphosphonates and dihydrogen acylphosphonates (acylphosphonic acids) have never been reported, and their chemical and physical properties have not been described. Assumptions about the chemical properties of acylphosphonic acids and of their monoesters have been based on the properties of the d i e~t e r s .~ Such extrapolations cannot be justified since ionization of the phosphoryl group should influence considerably the reactivity of the whole molecule. There exists information in the recent literature regarding the hydrolytic behaviour of specific and unusual acylphosphonic acids (see below), that can hardly be considered as representative compounds of their classes. In view of this, a systematic study of these acids is required, as it is a prerequisite to the design of novel biologically active compounds based upon these functional groups. Consequently we describe in this paper the preparation and physical and chemical properties of some representative acylphosphonic acids and monoesters. We have recently reported that acylphosphonic acids and monoesters undergo t...

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