UPPER III: unified physical property estimation relationships. Application to non-hydrogen bonding aromatic compounds.

The UPPER scheme uses four additive and two nonadditive parameters and several well-known equations to calculate 21 physical properties of organic compounds strictly from molecular structure. The scheme allows reasonable estimations of melting and boiling points, aqueous and octanol solubilities, air-octanol, air-water, and octanol-water partition coefficients, vapor pressure, and other properties. In this report non-hydrogen bonding aromatic compounds are used to evaluate a portion of the UPPER scheme.     

Percutaneous Permeation of Basic Compounds Through Shed Snake Skin as a Model Membrane

Abstract— Relationships between the in-vitro permeability of basic compounds through shed snake skin as a suitable model membrane for human stratum corneum and their physicochemical properties were investigated. Compounds with low pK_a values were selected to compare the permeabilities of non-ionized forms of the compounds. Steady-state penetration was achieved immediately without a lag time for all compounds. Flux rate and permeability coefficient were calculated from the steady-state penetration data and relationships between these parameters and the physicochemical properties were investigated. The results showed that permeability may be controlled by the lipophilicity and the molecular size of the compounds. Equations were developed to predict the permeability from the molecular weights and the partition coefficients of basic compounds.     

Estimation of Melting Points of Organics

Unified physicochemical property estimation relationships is a system of empirical and theoretical relationships that relate 20 physicochemical properties of organic molecules to each other and to chemical structure. Melting point is a key parameter in the unified physicochemical property estimation relationships scheme because it is a determinant of several other properties including vapor pressure, and solubility. This review describes the first-principals calculation of the melting points of organic compounds from structure. The calculation is based on the fact that the melting point, T_m, is equal to the ratio of the heat of melting, ΔH_m, to the entropy of melting, ΔS_m. The heat of melting is shown to be an additive constitutive property. However, the entropy of melting is not entirely group additive. It is primarily dependent on molecular geometry, including parameters which reflect the degree of restriction of molecular motion in the crystal to that of the liquid. Symmetry, eccentricity, chirality, flexibility, and hydrogen bonding, each affect molecular freedom in different ways and thus make different contributions to the total entropy of fusion. The relationships of these entropy determining parameters to chemical structure are used to develop a reasonably accurate means of predicting the melting points over 2000 compounds.     

De-Risking Early-Stage Drug Development With a Bespoke Lattice Energy Predictive Model: A Materials Science Informatics Approach to Address Challenges Associated With a Diverse Chemical Space

The solid-state properties of new chemical entities are critical to the stability and bioavailability of pharmaceutical drug products. The stability of the solid-state packing is described by the packing energy and an accurate prediction of this property for drug molecules would therefore be desirable. However, this has been difficult to achieve because of the lack of fundamental thermodynamic data on drug molecules. A potential solution would be to use calculated lattice energies to build a model and design molecules with desired physicochemical properties from an early stage, aligning with a “design by first intent” strategy for physicochemical properties. We first demonstrate the high correlation and interchangeability between QSPR models built using calculated lattice energies and experimental sublimation enthalpies for small organic molecules. We then present a QSPR model trained on in-house molecules using lattice energies calculated from crystal structures. The result is a model that enables fast prediction of the lattice energies of in-house molecules from 2-D molecular structure with reasonable accuracy (R² = 0.92, root mean square error = 3.58 kcal/mol). We explore the model elements to improve our understanding of the molecular properties that contribute to lattice energy and then suggest potential cross-industry aspects that may enhance the application of the concept.     

Physicochemical Parameters Responsible for the Affinity of Methotrexate Analogs for Rat Canalicular Multispecific Organic Anion Transporter (cMOAT/MRP2)

Purpose. Canalicular multispecific organic anion transporter (cMOAT/MRP2) is known to exhibit a broad substrate specificity toward amphiphatic organic anions, including methotrexate (MTX). The present study aims to identify the physicochemical properties of MTX derivatives that correlate with recognition specificity by cMOAT/MRP2. Methods. We examined the inhibitory effect of MTX and 24 analogs on the transport of [³H]–S–(2,4–dinitrophenyl)glutathione by cMOAT/MRP2. The affinity constants of these compounds were compared with their physicochemical parameters. The primary active transport of several compounds was also confirmed. Results. The affinity constants closely correlated with the octanol/water partition coefficient (clogP), and a linear combination of polar and nonpolar surface areas. The affinity for cMOAT/MRP2 also closely correlated with the molecular weight, which also showed a significant correlation with nonpolar surface area and clogP. Conclusions. Recognition by cMOAT/MRP2 depends on a balance of dynamic surface properties between the polar and nonpolar regions of MTX analogs. The so–called molecular weight threshold for the cMOAT/MRP2 affinity of these compounds can be explained by their physicochemical parameters, especially their nonpolar surface areas.     

The role of organic anion‐transporting polypeptides and formulation in the clearance and distribution of a novel Nav1.7 channel blocker

PF‐06456384 is an extremely potent and selective blocker of the Na_v1.7 sodium channel designed as a potential intravenous (i.v.) analgesic targeting high potency and rapid clearance to minimize the potential for residual effects following the end of infusion. In our previous experience targeting oral molecules, the requirement to obtain potent, Na_v1.7 selective molecules led to a focus on acidic, amphipilic compounds cleared primarily by organic anion‐transporting polypeptide mediated hepatic uptake and subsequent biliary excretion. However, the physicochemical properties of the i.v. lead matter were substantially different, moving from acidic, amphiphilic chemical space to zwitterions as well as substantially increasing molecular weight. This report describes the continued relevance of organic anion‐transporting polypeptide driven hepatic uptake in this physicochemical space and highlights an apparent impact of the formulation excipient Solutol on the clearance and distribution of PF‐06456384.     

Characteristics of drugs that penetrate the preimplantation blastocyst

Experiments were performed to evaluate the role of physicochemical properties of drugs and chemicals in determining their passage into the preimplantation blastocysts of 6-day pregnant rabbits. It was found that compounds with molecular weight less than ouabain (mol. wt 585) readily traversed the blastocyst, whereas the blastocyst was relatively impermeable to those with molecular weight greater than 5000. However, for compounds with small molecular weights (100–300), the blastocyst/plasma radioactivity ratios varied considerably (0.001–1.24), suggesting that factors other than molecular weight played a role in determining their passage. Further experiments revealed that there was no correlation between blastocyst/plasma radioactivity ratio and degree of protein binding of the drugs. It was concluded that the degree of ionization and lipid solubility of the compounds are important factors in determining their rates of penetration into the preimplantation blastocysts. These findings prove that a variety of foreign compounds can enter the blastocyst during the preimplantation stages of gestation and their rates of penetration are governed by the possible interactions among their physicochemical properties. The lexicological implications of these findings were also discussed.     

Estimation of melting points of organic compounds-II

A model for calculation of melting points of organic compounds from structure is described. The model utilizes additive, constitutive and nonadditive, constitutive molecular properties to calculate the enthalpy of melting and the entropy of melting, respectively. Application of the model to over 2200 compounds, including a number of drugs with complex structures, gives an average absolute error of 30.1 degrees.     

Encapsulation of Drug Molecules into Calix[n]arene Nanobaskets. Role of Aminocalix[n]arenes in Biopharmaceutical Field

Calix[n]arenes (CAs) are supramolecular compounds able to form guest-host inclusion complexes with metal ions, small organic molecules, and small moieties of larger molecules. Although the CA literature is extensive, relatively few publications deal with water-soluble CAs, especially those containing nitrogen-based functionality. These CAs possess antibacterial and antifungal activity. Because of their molecular structure, they are surface active and also able to form water-soluble drug complexes, giving additional potential as enabling pharmaceutical excipients. This article provides an overview of the published data regarding synthesis, physicochemical properties, and pharmaceutical application of water-soluble CAs with emphasis on those that contain nitrogen-based substituents in their structure, particularly aminoCAs. In particular, it describes state-of-the-art in complexation of water-soluble CAs with pharmaceutically relevant ions and organic molecules up to amino acids, DNA, and proteins.     

Chemoproteomics as a basis for post-genomic drug discovery

The large number of small organic compounds now available for drug-lead screening has led to numerous methods for classifying molecular similarity and diversity, the aim being to restore a balance between the quantity and drug-like quality of compounds in small-molecule libraries. Whereas structural and physicochemical attributes continue to be emphasized in compound selection for drug-lead screening, chemoproteomics--the use of biological information to guide chemistry--offers a highly efficient alternative to small-molecule characterization that can accelerate drug discovery in the post-genomic era.     

Predicting Plasticization Efficiency from Three-Dimensional Molecular Structure of a Polymer Plasticizer

Purpose. In polymeric coatings, plasticizers are used to improve the film-forming characteristic of the polymers. In this study, a computerized method (VolSurf with GRID) was used as a novel tool for the prediction plasticization efficiency () of test compounds, and for determining the critical molecular properties needed for polymer plasticization. Methods. The film-former, starch acetate DS 2.8 (SA), was plasticized with each of 24 tested compounds. A decrease in glass transition temperature of the plasticized free films (determined by differential scanning calorimeter (DSC)) was used as an indicator for . Partial least squares discriminant analysis was used to correlate the experimental data with the theoretical molecular properties of the plasticizers. Results. A good correlation (r² = 0.77, q² = 0.58) between the molecular modeling results and the experimental data demonstrated that can be predicted from the three-dimensional molecular structure of a compound. Favorable structural properties identified for the potent SA plasticizer were strong hydrogen bonding capacity and a definitive hydrophobic region on the molecule. Conclusions. The VolSurf method is a valuable tool for predicting the plasticization efficiency of a compound. The correlation between experimental and calculated glass transition temperature values verifies that physicochemical properties are primary factors influencing plasticization efficiency of a compound.     

The influence of the 'organizational factor' on compound quality in drug discovery

Physicochemical properties such as lipophilicity and molecular mass are known to have an important influence on the absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of small-molecule drug candidates. To assess the use of this knowledge in reducing the likelihood of compound-related attrition, the molecular properties of compounds acting at specific drug targets described in patents from leading pharmaceutical companies during the 2000-2010 period were analysed. Over the past decade, there has been little overall change in properties that influence ADMET outcomes, but there are marked differences in molecular properties between organizations, which are maintained when the targets pursued are taken into account. The target-unbiased molecular property differences, which are attributable to divergent corporate drug design strategies, are comparable to the differences between the major drug target classes. On the basis of our analysis, we conclude that a substantial sector of the pharmaceutical industry has not modified its drug design practices and is still producing compounds with suboptimal physicochemical profiles.