An underlying goal of drug discovery is to develop safe and stable substances that specifically target essential elements that cause disease. Molecular chirality adds an additional level of specificity and complexity in achieving this objective, as mirror image molecules are distinct substances and must be treated as such. Classical chiral-center enantiomers ( Figure 1A) have been shown to differ significantly in biological activity, pharmacodynamics, pharmacokinetics, and toxicity. 1 The cases of thalidomide 2 and perhexiline, 3 whose enantiomers differ dramatically with respect to toxicity and metabolic properties, emphasize the importance of addressing stereochemistry in drug development.In this Perspective, we address the pharmaceutical implications of a largely overlooked alternative source of drug chirality, atropisomerism, 4 which has the distinct feature of creating molecular chirality as a result of hindered rotation about a bond axis ( Figure 1B). Figure 1C shows space-filling models where it is evident that rotation about the vertical axis is hindered because of steric clashes between the bulky R1 and R2 groups with R3 and R4.Unlike compounds with classical chiral centers, which are often stable and which racemize via a bond breaking and making process, atropisomers racemize via an intramolecular dynamic process that only involves bond rotation. As bond rotation is time-dependent, racemization half-lives for atropisomers can vary dramatically between minutes to years, depending on the degree of steric hindrance, electronic influences, temperature, solvent, etc. Because of this time-dependent feature, drug discovery campaigns can become more complex, or may even be abandoned, when atropisomeric properties are observed. Atropisomerism frequently results as researchers strive to design more compact and conformationally constrained inhibitors. Even for courageous design and synthetic campaigns that attempt to develop atropisomeric compounds, important differences in properties have been reported for enantiomeric pairs, such as in vitro inhibition, crystallization, in vivo racemization rates, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. There are also examples of compounds that were unknowingly developed as a racemic mixture of atropisomers and required chiral detection experiments to finally reveal their existence. Overall, many view atropisomer chirality as a lurking menace with the potential to increase the cost of pharmaceutical research and development and to derail drug Figure 1. (A) Mirror-image enantiomers S and R arise from a classical chiral center (atom). (B) Other enantiomers S a and R a can arise from hindered rotation that creates a chiral axis. (C) Atropisomeric enantiomers S a and R a are shown as space-filling models. Reproduced with permission from ChemMedChem (LaPlante, S. R.; Edwards, P. J.; Fader, L. D.; Jakalian, A.; Hucke, O. Revealing atropisomer axial chirality in drug discovery. 2011, 6, 505À513,

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Molecular evolution is moving from statistical descriptions of adaptive molecular changes toward predicting the fitness effects of mutations. Here, we characterize the fitness landscape of the six amino acids controlling coenzyme use in isopropylmalate dehydrogenase (IMDH). Although all natural IMDHs use nicotinamide adenine dinucleotide (NAD) as a coenzyme, they can be engineered to use nicotinamide adenine dinucleotide phosphate (NADP) instead. Intermediates between these two phenotypic extremes show that each amino acid contributes additively to enzyme function, with epistatic contributions confined to fitness. The genotype-phenotype-fitness map shows that NAD use is a global optimum.

breed differences for feed efficiency, growth, and body composition traits of young beef bulls. Can. J. Anim. Sci. 84: 177-185. Genetic associations between feed efficiency, growth, and live ultrasound measured body composition traits were studied in purebred beef bulls of six breeds in Ontario bull test stations from 1991 to 2000. Feed traits included average daily feed intake (FI), feed conversion ratio (FCR), and residual feed intake [feed intake adjusted for production alone (RFIp) or production and backfat thickness (RFIb)]. Growth traits were average daily weight gain (ADG), mid-test metabolic weight (MW), hip height (HH), and scrotal circumference (SC). Body composition traits included ultrasound backfat thickness (BF), longissimus muscle area (LMA), and predicted percentage of intramuscular fat (IFAT). Bulls were measured every 28 d for weight and individual feed intake, and at the end of test for ultrasound body composition traits. Number of records per trait ranged from 2284 (FI) to 13 319 (ADG). Fixed effects of test group, breed and end of test age (within breed), and random effects of animal and herd of origin were modeled using REML bivariate analyses for all traits. Heritability estimates were moderate for all traits (0.30 to 0.55), except for IFAT (0.14). The genetic correlation between RFIp and RFIb was high (0.99) within breeds, but breeds ranked differently with respect to RFIp and RFIb. Genetic correlations of RFIb with ADG and backfat thickness were essentially zero, which indicate that selection on residual feed intake could be implemented to reduce feed intake and improve feed conversion without compromising growth or changing levels of subcutaneous fat.