Source: Ghose, A. K., Viswanadhan, V. N., and Wendoloski, J. J.: J. Comb. Chem. 1:55, 1999.

Source: Ghose, A. K., Viswanadhan, V. N., and Wendoloski, J. J.: J. Comb. Chem. 1:55, 1999.

dimensions and physicochemical characteristic. Keeping in mind that the receptor is a protein, there will be hydrogen bond acceptors and donors (serine, threonine, tyrosine), positively and negatively charged side chains (lysine, histidine, glutamic acid, aspartic acid), nonpolar or hydrophobic side chains (leucine, isoleucine, valine, alanine), and induced dipoles (phenylalanine, tyrosine). The type of groups that will be attracted or repulsed by the type of amino acid side chain is coded into the chemical database. The virtual screening will lead to development of a refined model for good binding, and the search is repeated. When the model is considered valid, it must be tested by actual screening in biological test systems and by synthesizing new compounds to test its validity.

Another approach to searching a database of compounds is the use of the chemical fragments described earlier. There is ongoing debate regarding what type of fragments will result in the most hits. Nevertheless, there now are fragment libraries constructed around the range of the fragments' physicochemical properties, solubilities, molecular diversity, and drug likeness based on their presence in existing compounds.46

Figure 2.26 • High-throughput screening.


In the process of designing new pharmacologically active compounds or searching databases, it is important to not restrict the definition of the structures to specific atoms. An important concept is isosterism, a term that has been used widely to describe the selection of structural components—the steric, electronic, and solubility characteristics that make them interchangeable in drugs of the same pharmacological class. The concept of isosterism has evolved and changed significantly in the years since its introduction by Langmuir in 1919.47 Langmuir, while seeking a correlation that would explain similarities in physical properties for nonisomeric molecules, defined isosteres as compounds or groups of atoms having the same number and arrangement of electrons. Isosteres that were isoelectric (i.e., with the same total charge as well as the same number of electrons) would possess similar physical properties. For example, the molecules N2 and CO both possess 14 total electrons and no charge and show similar physical properties. Related examples described by Langmuir were CO2, N2O, N3", and NCO" (Table 2.11).

With increased understanding of the structures of molecules, less emphasis has been placed on the number of electrons involved, because variations in hybridization during bond formation may lead to considerable differences in the angles, lengths, and polarities of bonds formed by atoms with the same number of peripheral electrons. Even the same atom may vary widely in its structural and electronic characteristics when it forms part of a different functional group. Thus, nitrogen is part of a planar structure in the nitro group but forms the apex of a pyramidal structure in ammonia and amines.

Groups of atoms that impart similar physical or chemical properties to a molecule because of similarities in size, electronegativity, or stereochemistry are now frequently referred to by the general term of isostere. The early recognition that benzene and thiophene were alike in many of their properties (Fig. 2.27) led to the term ring equivalents for the vinylene group (—CH=CH—) and divalent sulfur (—S—). This concept has led to replacement of the sulfur atom in the phenothi-azine ring system of tranquilizing agents with the vinylene

TABLE 2.11 Commonly Used Alicyclic Chemical Isosteres

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