Homodimer design

The HIV-l protease is a remarkable viral imitation of mammalian aspartic proteases It is a dimer of identical subunits that mimics the two-lobed monomeric structure of pepsin and other aspartic proteases. The HIV-l protease subunits are 99-residue polypeptides that are homologous with the individual domains of the monomeric proteases. Structures determined by X-ray diffraction studies reveal that the active site of HIV-l protease is formed at the interface of the homodimer and consists of two aspartate residues, designated Asp and Asp one contributed by each subunit (Figure 16.29). In the homodimer, the active site is covered by two identical flaps, one from each subunit, in contrast to the monomeric aspartic proteases, which possess only a single active-site flap. 

Coil-Ser A Peptide Designed as Parallel Homodimer that Forms an Up-Up-Down Homotrimer (1990)... 

If the size of the proteome is P, there will be no more than Pn possible n- mer interactions. However, as far as drug design is concerned, the size of the interacting surfaces that could be interfered with by a small molecule is small and unlikely to include three proteins this limits the potential number of interactions to P2. If the human proteome contains 105 proteins, the number of homodimer interactions is potentially 1010. 

Despite sharing only 25% sequence identity, structural analysis indicates that both proteins of E. coli NADP-IDH and T. thermophilus NAD-IMDH are homodimers which share a common protein fold that lacks the p p p motif characteristic of the nucleotide binding Rossmann fold [23], The strict and distinct specificities of these enzymes provide an attractive model system for engineering specificity, while the extensive knowledge of substrate and coenzyme binding and catalysis provide the sound foundation critical for rational design. 

Recently Richardson and Richardson (1987) have designed a protein that is intended to adopt an antiparallel /3-barrel structure similar to that of an immunoglobulin VL domain (Fig. 22). To aid in the chemical synthesis of the molecule, the protein was designed as a homodimer of two identical chains connected by an organic cross-linking moiety. The model for the designed protein is highly symmetrical (Fig. 22), with a 2-fold rotational... 

A unique biochemical target in the HIV-1 replication cycle was revealed when HIV protease was cloned and expressed " in Escherichia coli. HIV protease is an enzyme that cleaves gag-pro propeptides to yield active enzymes that function in the maturation and propagation of new virus. The catalytically active protca.se is a. symmetric dimer of two identical 99 amino acid subunits, each contributing the triad Asp-Thr-Gly to the active site." The homodimer is unlike monomeric asparlyl protea.ses (renin, pepsin, cathep-sin D). which also have different. substrate specificities. The designs of. some inhibitors for HIV-1 protease exploit the C2 symmetry of the enzyme. HIV-1 protease has active site speclnc ity for the triad Tyr-Phe-Pro in the unit Ser-(Thr)-Xaa-Xaa-Tyr-Phc-Pm. whenr Xaa is an arbitrary amino acid. 

The association of two identical pharmacophoric entities will generate an identical twin drug which is equivalent to a homodimer derivative. A compound, where two different pharmacological entities are bounded, is called a non-identical twin drug or heterodimer. The first design strategy is equivalent to a duplication/dimerization process of an active compound or lead. The aim of this approach is the production of a more potent and/or more selective drug... 

The design of bifunctional AChE inhibitors was achieved in order to obtain potent and selective derivatives. Tacrine, an AChE inhibitor used for the treatment of Alzheimer disease (AD) patients, has been dimerized leading to the bis- 3Lcnnt derivative (Eigure 18.17). The length of the methylene chain was optimized in order to obtain a potent and selective homodimer. ilA-tetrahydroaminacrine... 

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