ABSTRACT
We developed an algorithm (ANDI) for predicting regulatory marketing approval for new cancer drugs after phase II testing has been conducted, with the objective of providing a tool to improve drug portfolio decision-making. We examined 98 oncology drugs from the top 50 pharmaceutical companies (2006 sales) that first entered clinical development from 1999 to 2007, had been taken to at least phase II development, and had a known final outcome (research abandonment or regulatory marketing approval). Data on safety, efficacy, operational, market, and company characteristics were obtained from public sources. Logistic regression and machine-learning methods were used to provide an unbiased approach to assess overall predictability and to identify the most important individual predictors. We found that a simple four-factor model (activity, number of patients in the pivotal phase II trial, phase II duration, and a prevalence-related measure) had high sensitivity and specificity for predicting regulatory marketing approval.
Subject(s)
Algorithms , Antineoplastic Agents/therapeutic use , Clinical Trials, Phase II as Topic/legislation & jurisprudence , Drug Approval/legislation & jurisprudence , Machine Learning , Clinical Trials, Phase II as Topic/methods , Drug Approval/methods , Forecasting , Humans , Neoplasms/diagnosis , Neoplasms/drug therapyABSTRACT
Assigning absolute configuration of molecules continues to be a major problem. Determining absolute configuration in conformationally flexible systems is challenging, even for experts. Here, we present a case study in which we use a combination of molecular modeling, solution NMR, and X-ray crystallography to illustrate why it is difficult to use solution methods alone for configuration assignment. For the case examined, a comparison of calculated and experimental optical rotatory dispersion (ORD) data provides the most straightforward way to assign the absolute configuration.
Subject(s)
Benzoates/chemistry , Naphthalenes/chemistry , Optical Rotatory Dispersion/methods , Circular Dichroism , Crystallography, X-Ray , Molecular Conformation , Solutions , Stereoisomerism , ThermodynamicsABSTRACT
[structure--see text] Calyculins A and B differ only by the (E)- vs (Z)-configuration at C(2). Yet, they show a large difference in optical rotations. We demonstrate a new strategy that provides a physical analysis of this long-range chiro-optical effect by Boltzmann-averaged atomic contribution mapping. The polarizability characteristics of the CN substituent rather than the perturbation of the stereogenic centers or the introduction of asymmetry into the polyene chain give rise to the remarkable difference in rotation angles.
Subject(s)
Organophosphates/chemistry , Oxazoles/chemistry , Biological Factors/chemistry , Carcinogens/chemistry , Enzyme Inhibitors/chemistry , Marine Toxins , Models, Molecular , Molecular Conformation , Optical Rotation , Phosphoprotein Phosphatases/antagonists & inhibitors , Stereoisomerism , Thermodynamics , Vasoconstrictor Agents/chemistryABSTRACT
Chiral molecules are characterized by a specific rotation angle, the angle through which plane-polarized light is rotated on passing through an enantiomerically enriched solution. Recent developments in methodology allow computation of both the sign and the magnitude of these rotation angles. However, a general strategy for assigning the individual contributions that atoms and functional groups make to the optical rotation angle and, more generally, to the molecular chirality has remained elusive. Here, a method to determine the atomic contributions to the optical rotation angle is reported. This approach links chemical structure with optical rotation angle and provides a quantitative measure of molecular asymmetry propagation from a center, axis, or plane of chirality.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Ethylene Oxide/chemistry , Hexanes/chemistry , Optical Rotation , Stereoisomerism , Ethylene Oxide/analogs & derivatives , Mathematics , Models, Chemical , Molecular Conformation , Molecular Structure , Quantum TheoryABSTRACT
When plane-polarized light impinges on a solution of optically active molecules, the polarization of the light that emerges is rotated. This simple phenomenon arises from the interaction of light with matter and is well understood, in principle, van't Hoff's rule of optical superposition correlates the molar rotation with the individual contributions to optical activity of isolated centers of asymmetry. This straightforward empirical additivity rule is rarely used for structure elucidation nowadays because of its limitations in the assessment of conformationally restricted or interacting chiral centers. However, additivity can be used successfully to assign the configuration of complex natural products such as hennoxazole A if appropriate synthetic partial structures are available. Therefore, van't Hoff's principle is a powerful stereochemical complement to natural products' total synthesis. The quest for reliable quantitative methods to calculate the angle of rotation a priori has been underway for a long time. Both classical and quantum methods for calculating molar rotation have been developed. Of particular practical importance for determining the absolute structure of molecules by calculation is the manner in which interactions between multiple chiral centers in a single molecule are included, leading to additive or non-additive optical rotation angles. This problem is addressed here using semi-empirical electronic structure models and the Rosenfeld equation.
