Many metrics are currently used to evaluate the performance of ranking methods in virtual screening (VS), for instance, the area under the receiver operating characteristic curve (ROC), the area under the accumulation curve (AUAC), the average rank of actives, the enrichment factor (EF), and the robust initial enhancement (RIE) proposed by Sheridan et al. In this work, we show that the ROC, the AUAC, and the average rank metrics have the same inappropriate behaviors that make them poor metrics for comparing VS methods whose purpose is to rank actives early in an ordered list (the "early recognition problem"). In doing so, we derive mathematical formulas that relate those metrics together. Moreover, we show that the EF metric is not sensitive to ranking performance before and after the cutoff. Instead, we formally generalize the ROC metric to the early recognition problem which leads us to propose a novel metric called the Boltzmann-enhanced discrimination of receiver operating characteristic that turns out to contain the discrimination power of the RIE metric but incorporates the statistical significance from ROC and its well-behaved boundaries. Finally, two major sources of errors, namely, the statistical error and the "saturation effects", are examined. This leads to practical recommendations for the number of actives, the number of inactives, and the "early recognition" importance parameter that one should use when comparing ranking methods. Although this work is applied specifically to VS, it is general and can be used to analyze any method that needs to segregate actives toward the front of a rank-ordered list.

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This review brings to the forefront key synthetic modifications on natural products (NPs) that have yielded successful drugs. The emphasis is placed on the power of targeted chemical transformations in enhancing the therapeutic value of NPs through optimization of pharmacokinetics, stability, potency, and/or selectivity. Multiple classes of NPs such as macrolides, opioids, steroids, and β-lactams used to treat a variety of conditions such as cancers, infections, inflammation are exemplified. Molecular modeling or X-ray structures of NP/protein complexes supporting the observed boost in therapeutic value of the modified NPs are also discussed. Significant advancement in synthetic chemistry, in structure determination, and in the understanding of factors controlling pharmacokinetics can now better position drug discovery teams to undertake NPs as valuable leads. We hope that the beneficial NPs synthetic modifications outlined here will reignite medicinal chemists' interest in NPs and their derivatives.

A novel approach for representing the intramolecular polarizability as a continuum dielectric is introduced to account for molecular electronic polarization. It is shown, using a finite-difference solution to the Poisson equation, that the Electronic Polarization from Internal Continuum (EPIC) model yields accurate gas-phase molecular polarizability tensors for a test set of 98 challenging molecules composed of heteroaromatics, alkanes and diatomics. The electronic polarization originates from a high intramolecular dielectric that produces polarizabilities consistent with B3LYP/aug-cc-pVTZ and experimental values when surrounded by vacuum dielectric. In contrast to other approaches to model electronic polarization, this simple model avoids the polarizability catastrophe and accurately calculates molecular anisotropy with the use of very few fitted parameters and without resorting to auxiliary sites or anisotropic atomic centers. On average, the unsigned error in the average polarizability and anisotropy compared to B3LYP are 2% and 5%, respectively. The correlation between the polarizability components from B3LYP and this approach lead to a R2 of 0.990 and a slope of 0.999. Even the F2 anisotropy, shown to be a difficult case for existing polarizability models, can be reproduced within 2% error. In addition to providing new parameters for a rapid method directly applicable to the calculation of polarizabilities, this work extends the widely used Poisson equation to areas where accurate molecular polarizabilities matter.