Thermodynamic descriptors

CODESSA can compute or import over 500 molecular descriptors. These can be categorized into constitutional, topological, geometric, electrostatic, quantum chemical, and thermodynamic descriptors. There are automated procedures that will omit missing or bad descriptors. Alternatively, the user can manually define any subset of structures or descriptors to be used. 

A volume-related term (expressed by polarizability) and electrostatics (expressed by partial atomic charge) made minor contributions to intestinal absorption in humans. Lipophilicity, expressed by logP or logD values, shows no correlation with the human absorphon data. Recently, similar results were obtained for 154 passively transported drugs on the basis of surface thermodynamics descriptors [39] ... 

Log P and MR are considered thermodynamic descriptors, pR a combined thermodynamic and electronic index, and a an electronic property index, E is designed to account for steric effects. Corrections for non-additivity, based upon the chemical bonding topology, have been suggested and used. These include proximity, bond type, ring, and group shape correction features. (8-10)... 

CODESSA Constitutional, topological, geometrical, electrostatic, surface property, quantum chemical, and thermodynamic descriptors 1,500... 

For a measure of amount of water relevant to stability concerns, vapor pressure, or its related thermodynamic parameters, is more relevant. Determination of vapor pressure uses methods developed from thermodynamic roots, though if the product is not at true equilibrium, the measured quantity is not a thermodynamic descriptor of the product, although it is still a measure of a product characteristic. Water mobilities are often inferred from spectroscopic measurements of relaxational phenomena. Many workers attempt to identify different classes of water characteristic of different ranges of water content and water partial vapor pressure. Spectroscopic measurements, too, are often interpreted in terms of populations of water molecules with similar characteristics. 

Govers, H.A.J., Parsons, J.R., Krop, H.B., and Cheung, C.L., Thermodynamic descriptors for (bio-)degradation, Proc. Workshop Quant. Struct. Act. Relat. Biodegradation (September 1994, Belgirate, Italy), Report No. 719101021, National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands, 1995. 

Thermodynamic descriptors AlogP98, logarithm of the octanol/water partition coefficient, atom-type value the AlogP98 descriptor is an implementation of the atom-type-based AlogP method using the latest published set of parameters. 

The two amino acids sets have been grouped in 3D topological and chemical-physical space, on the basis, not only of topological descriptors and AlogPgg (Figure 3.12), but also on the basis of structural, electronic and thermodynamic descriptors (Figure 3.13). 

Piguet C. Chapter 272 — Microscopic thermodynamic descriptors for rationalizing lanthanide complexation processes. In Biinzli J-C, Pecharsky VK, eds. Handbook on the Physics and Chemistry of Rare Earths. Amsterdam, The Netherlands Ekevier 2015 209-271 vol. 47. 

Before embarking on a description of the computational methods involved, and how well they perform, we should address the goals of crystal structure prediction. At its most ambitious level, the aim is to start from nothing more than the structural formula of a molecule and to predict, with perfect reliability, the structure of the resulting solid, with no input from experimental observations. (Here, by structure, we mean the space group, unit cell parameters and a fiiU specification of all atomic positions.) This goal is, of course, unrealistic polymorphism in molecular crystals tells us that there is often not just one crystal structure for a molecule and we know that the crystal that is produced in an experiment depends on a variety of factors, from thermodynamic descriptors of the system (temperature and pressure) to the method of crystallization, solvent used and the presence of impurities. Without a detailed description of the crystallization conditions, prediction of the resulting structure cannot be the aim. Furthermore, many of these factors are not sufficiently well understood to be represented in a computational procedure for crystal structure prediction. 

HYBOT-Plus (hydrogen bonding thermodynamics, calculation of local and molecular physicochemical descriptors) http //www.timtec.net/soJiware/hybot-plus.htm... 

Molecular descriptors must then be computed. Any numerical value that describes the molecule could be used. Many descriptors are obtained from molecular mechanics or semiempirical calculations. Energies, population analysis, and vibrational frequency analysis with its associated thermodynamic quantities are often obtained this way. Ah initio results can be used reliably, but are often avoided due to the large amount of computation necessary. The largest percentage of descriptors are easily determined values, such as molecular weights, topological indexes, moments of inertia, and so on. Table 30.1 lists some of the descriptors that have been found to be useful in previous studies. These are discussed in more detail in the review articles listed in the bibliography. 

Two-dimensional H-bond descriptors are included in Table 6.1. Considering information content, they may be classified as indirect descriptors (no direct link with the H-bonding process), H-bond indicators (atoms having potential H-bond capability) and thermodynamic factors (calculated on the basis of experimental thermodynamic data of H-bonding). 

PSA. Hence, we only mention here that the definition of PSA is similar to that of Na and N. Thus, PSA possesses the same disadvantages when compared to thermodynamic H-bond descriptors. In fact, it has been estimated that there is a strong linear relationship between the calculated static PSA and the calculated dynamic polar surface [32, 33]. A further possible simplification using only the number of H-bond forming atoms and PLS statistics was proposed [35]. Excellent correlahons of PSA with the number of H-bond donors and acceptors were published [35, 36]. 

The pKa of a molecule, a charge-state-related parameter, is a descriptor of an acid-base equilibrium reaction [34,35]. Lipophilicity, often represented by the octanol-water partition coefficient Kp is a descriptor of a two-phase distribution equilibrium reaction [36]. So is solubility [37-39]. These three parameters are thermodynamic constants. On the other hand, permeability Pe is a rate coefficient, a kinetics parameter, most often posed in a first-order distribution reaction [40-42]. 

In the following section, the calculation of the VolSurf parameters from GRID interaction energies will be explained and the physico-chemical relevance of these novel descriptors demonstrated by correlation with measured absorption/ distribution/metabolism/elimination (ADME) properties. The applications will be shown by correlating 3D molecular structures with Caco-2 cell permeabilities, thermodynamic solubilities and metabolic stabilities. Special emphasis will be placed on interpretation of the models by multivariate statistics, because a rational design to improve molecular properties is critically dependent on an understanding of how molecular features influence physico-chemical and ADME properties. 

On the other hand, there is considerable interest to quantify the similarities between different molecules, in particular, in pharmacology [7], For instance, the search for a new drug may include a comparative analysis of an active molecule with a large molecular library by using combinatorial chemistry. A computational comparison based on the similarity of empirical data (structural parameters, molecular surfaces, thermodynamical data, etc.) is often used as a prescreening. Because the DFT reactivity descriptors measure intrinsic properties of a molecular moiety, they are in fact chemical fingerprints of molecules. These descriptors establish a useful scale of similarity between the members of a large molecular family (see in particular Chapter 15) [18-21],... 

These descriptors have been widely used for the past 25 years to study chemical reactivity, i.e., the propensity of atoms, molecules, surfaces to interact with one or more reaction partners with formation or rupture of one or more covalent bonds. Kinetic and/or thermodynamic aspects, depending on the (not always obvious and even not univoque) choice of the descriptors were hereby considered. In these studies, the reactivity descriptors were used as such or within the context of some principles of which Sanderson s electronegativity equalization principle [16], Pearson s hard and soft acids and bases (HSAB) principle [17], and the maximum hardness principle [17,18] are the three best known and popular examples. 

In this chapter, the diverse coupling constants and MEC components identified in the combined electronic-nuclear approach to equilibrium states in molecules and reactants are explored. The reactivity implications of these derivative descriptors of the interaction between the electronic and geometric aspects of the molecular structure will be commented upon within both the EP and EF perspectives. We begin this analysis with a brief survey of the basic concepts and relations of the generalized compliant description of molecular systems, which simultaneously involves the electronic and nuclear degrees-of-freedom. Illustrative numerical data of these derivative properties for selected polyatomic molecules, taken from the recent computational analysis (Nalewajski et al., 2008), will also be discussed from the point of view of their possible applications as reactivity criteria and interpreted as manifestations of the LeChatelier-Braun principle of thermodynamics (Callen, 1962). 

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