Drug-like molecule

Many drug-like molecules have aromatic substituents and thus have limited aqueous solubility. A routine practice is to dissolve stock drugs in a solvent known to dissolve many types of molecular structures. One such solvent is... 

Singh SB, Shen LQ, Walker MJ, Sheridan RP. A model for likely sites of CYP3A4-mediated metabolism on drug-like molecules. J Med Chem 2003 46 1330-6. 

Ajay Walters, W.P., Murcko, M.A. (1998) Can we Learn to Distinguish between Drug-like and Non-Drug-like Molecules Journal of Medicinal Chemistry, 41, 3314—3224. 

Blake, J. F. Chemoinformatics -predicting the physicochemical properties of drug-like molecules. Curr. Opin. Biotechnol. 2000, 11, 104-107. 

This chapter considered ionizable drug-like molecules. Absorption properties that are influenced by the pKj were explored. The impact of the pKj-absorption relationship on key physicochemical profiling underlying absorption (solubihty, per-meabihty and ionization) was examined in detail and several simpUfying equations were discussed. The various diff relationships considered in the chapter are systematized in Table 3.2. Table 3.3 summarizes the apparent pfQ shift method for detecting aggregates in solubility profiles, when the apparent pff value derived from Henderson-Hasselbalch analysis of log S pH profile does not agree with the... 

Most drug-like molecules adopt a number of conformations through rotations about bonds and/or inversions about atomic centers, giving the molecules a number of different three-dimensional (3D) shapes. To obtain different energy minimized structures using a force field, a conformational search technique must be combined with the local geometry optimization described in the previous section. Many such methods have been formulated, and they can be broadly classified as either systematic or stochastic algorithms. 

Perola, E., Charifson, P. S. Conformational analysis of drug-like molecules bound to proteins an extensive study of ligand reorganization upon binding. /. Med. Chem. 2004, 47, 2499-2510. 

Nuclear magnetic resonance (NMR) spectroscopy is, next to X-ray diffraction, the most important method to elucidate molecular structures of small molecules up to large bio macromolecules. It is used as a routine method in every chemical laboratory and it is not the aim of this article to give a comprehensive review about NMR in structural analysis. We will concentrate here on liquid-state applications with respect to drugs or drug-like molecules to emphasize techniques for conformational analysis including recent developments in the field. 

Elucidation of the stereostructure - configuration and conformation - is the next step in structural analysis. Three main parameters are used to elucidate the stereochemistry. Scalar coupling constants (mainly vicinal couplings) provide informa-hon about dihedral bond angles within a structure. Another way to obtain this information is the use of cross-correlated relaxation (CCR), but this is rarely used for drug or drug-like molecules. 

Fig. 9.1 The internuclear transfer of magnetization via NOE cross-relaxation in an isolated spin-pair. (A) Build-up curves for the cross-peak intensity in a 2D NOESY experiment for various internuclear distances r. The dashed line indicates a typical mixing time tm = 300rns used for drug-like molecules.

In summary, such simple classification schemes for drug-likeness can, in a very fast and robust manner, help to enrich compound selections with drug-like molecules. These filters are very general and cannot be interpreted any further. Thus, they are seen rather as a complement to the more in-depth profiling of leads and drugs by using molecular properties and identifying trends in compound series. 

The attractiveness of enzymes as drug targets results not only from the essentiality of their catalytic activity but also from the fact that enzymes, by their very nature, are highly amenable to inhibition by small molecular weight, drug-like molecules. Because of this susceptibility to inhibition by small molecule drugs,... 

Active sites amenable to binding drug-like molecules. 

The blue book compilations [154-158] are probably the most comprehensive sources of ionization constants collected from the literature (up to the end of 1970s). These are recommended for experts in the field. On the other hand, the red books contain critically selected values [159]. The six-volume set has been put into electronic form in cooperation with NIST (National Institute of Standards and Technology), and is available at a very reasonable price [160]. A two-volume set of critically determined constants is available from Sirius Analytical Instalments Ltd., and covers molecules of particular interest to the pharmaceutical community [161,162]. In Section 3.8 at the end of this chapter, a list of gold standard pKa values of mostly drug-like molecules is presented (see Table 3.1), with many of the values determined by the author since the early 1970s. 

Figures 7.31a-c clearly show that after some critical soy content in dodecane, Pe values decrease with increasing soy, for both sink and sinkless conditions. [This is not due to a neglect of membrane retention, as partly may be the case in Fig. 7.23 permeabilities here have been calculated with Eq. (7.21).] Section 7.6 discusses the Kubinyi bilinear model (Fig. 7.19d) in terms of a three-compartment system water, oil of moderate lipophilicity, and oil of high lipophilicity. Since lipo-some(phospholipid)-water partition coefficients (Chapter 5) are generally higher than alkane-water partition coefficients (Chapter 4) for drug-like molecules, soy lecithin may be assumed to be more lipophilic than dodecane. It appears that the increase in soy concentration in dodecane can be treated by the Kubinyi analysis. In the original analysis [23], two different lipid phases are selected at a fixed ratio (e.g., Fig. 7.20), and different molecules are picked over a range of lipophilicities.

Most drug-like molecules dissolved in water form hydrogen bonds with the solvent. When such a molecule transfers from water into a phospholipid bilayer, the solute-water hydrogen bonds are broken (desolvation), as new solute-lipid H bonds form in the lipid phase. The free-energy difference between the two states of solvation has direct impact on the ability of the molecules to cross biological barriers. 

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