Fragment replacement

An alternative approach to obtaining a starting model for the refinement that does not need NOE data is called molecular fragment replacement [71] and treats the protein of interest as overlapping fragments of 7 to 10 residues in length. A protein database is... 

Fig. 8.11 Illustration of the basic steps followed by the Molecular Fragment Replacement method to build a model of the structure of the protein Dinl.

Thus, the monofluoroalkene moiety is a non-hydrolysable isostere of the pep-tidic bond, and hence can be used as a peptidomimetic unit in the design of protease inhibitors [59,60]. This type of rigid isosteres of the peptidic bond can facilitate the cisjtrans conformational control of the fragment replaced. Because of the double bond, the bond length and angles of the peptidic bond are suitably mimicked, and the fluorine atom complements the analogy for electronic properties. This approach has been developed in the case of prolylamide fragments, in... 

Finally, we note a report of the synthesis and structure of a mixed transition metal-indium complex containing iron and manganese derived from the reaction between [Hg Mn(CO)5 2], [Fe(CO)5], and indium metal, viz. [ Fe(CO)4 2 /i-InMn(CO)5 2], 16 (27) (see Fig. 5). This complex is structurally similar to the manganese-indium complex 11 with each Mn(CO)4 fragment replaced in 16 by an Fe(CO)4 moiety. The increase in the electron count by two has been assumed to account for the absence of a Fe—Fe bond in 16 in contrast to the suggested presence of a corresponding Mn—Mn... 

As the BN unit is isoelectronic with a C2 fragment, replacement of the latter by the former in various organic compounds leads to azaborane structural analogs. Some examples are shown below. Planar borazine (or borazole) B3N3H6 is stabilized by n -delocalization, but it is much more reactive than benzene in view of the partial positive and negative charges on the N and B atoms, respectively. 

Kontaxis G, Delaglio F, Bax A. Molecular fragment replacement approach to protein structure determination by chemical 33. 

Delaglio F, Kontaxis G, Bax A (2000) Protein structure determination using molecular fragment replacement and NMR dipolar couplings. J Am Chem Soc 122 2142-2143... 

Hydrogenation of an alkene is an example of an addition, one of the three major reaction types we have studied addition, elimination, and substitution. In an addition, two molecules combine to form one product molecule. When an alkene undergoes addition, two groups add to the carbon atoms of the double bond and the carbons become saturated. In many ways, addition is the reverse of elimination, in which one molecule splits into two fragment molecules. In a substitution, one fragment replaces another fragment in a molecule. 

The Myers-Saito cyclization was first described independently in 1989 by Isao Saito (Kyoto University, Japan) and Andrew G. Myers (California Institute of Technology, Pasadena) whose findings were submitted for publication on June 7 and June 12, respectively. As a parallel transformation to the Moore cyclization (Chapter 4.12), in which an allenic fragment replaces the ketene moiety in the substrate, the Myers-Saito reaction provides a path to carbon diradicals. In its pioneering version, the reaction involved the cyclization of (Z)-l,2,4-heptatrien-6-yne (enyne-allene) 3, or its phosphine oxide derivative 5, to substituted a,3-dehydrotoluene diradicals, and subsequently to toluene derivatives 4 and 6. The reaction proceeds under thermal neutral conditions in 1,4-cyclohexadiene or other organic solvents such as methanol or carbon tetrachloride. 

Rescaffolding, bioisosteric replacement, or fragment replacement all describe workflows where a part of a molecule is replaced by another chemical moiety by retaining the biological activity [13]. The aim of this process is the design of molecules with novel IP or different properties. This concept has a long history in medicinal chemistry, but recently this process is heavily supported by methods of computational chemistry. Based on the retrospective evaluation of COX inhibitors, we will discuss this approach in more detail. 

Related to metalabenzenes are metaUoles, where the metal fragment replaces the NH of the heteroarene, pyrrole. On a strongly back-donating metal, the metallole of Eq. 5.47 has bis-carbene character. The X-ray structure shows that the complex has the bis-carbene structure, 5.32, and not the usual metallole structure, 5.33. The carbocycle in 5.32 is a 4e ligand, but in 5.33 is a 2e ligand, so this conversion can happen only if the metal can accept 2e. On the ionic model, both hgands are counted as 4e ligands, but the metal is counted as Os(II) in 5.32 and Os(IV) in 5.33, on both models. 5.32 is an 18e complex and 5.33 is a 16e complex. 

The CH2 fragment can use its two orbitals and two holes quite flexibly by changing its hybridization. If CH2 binds two H atoms to give CH4, sp hybridization now applies, but if it binds to a second CH2 to give C2H4, then sp hybrids form the a bonds and a p orbital forms the t bond. Mo(CO)5 is isolobal with CH2 because it also has two orbitals and two holes. The empty orbital is the 2e vacancy at the metal and the other is a orbital normally involved in back bonding. Fischer car-benes (CO)5Mo=CR2 show how the Mo(CO)5 fragment replaces one CR2 in the alkene R2C=CR2. 

Within a CFa-CFa fragment, replacement of fluorine by chlorine causes a... 

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