De-novo design

De novo design approaches computationally generate virtual molecules based on protein active sites or simply just de noco-designed molecules [39]. 

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Some aspects, such as the computer representation and manipulation of proteins and nucleic acids, could not be covered. Even the modeling of the interactions of small molecules with proteins, as dealt with in docking software or software for de novo design could not be included in the Textbook, although chapters in the Handbook do treat these subjects. 

Lonally, the templates were chosen by trial and error or exhaustive enumeration. A itafional method named ZEBEDDE (ZEolites By Evolutionary De novo DEsign) en developed to try to introduce some rationale into the selection of templates et al. 1996 Willock et al. 1997]. The templates are grown within the zeolite by an iterative inside-out approach, starting from a seed molecule. At each jn an action is randomly selected from a list that includes the addition of new (from a library of fragments), random translation or rotation, random bond rota-ing formation or energy minimisation of the template. A cost function based on erlap of van der Waals spheres is used to control the growth of the template ale ... 

H-J 1998. Prediction of Binding Constants of Protein Ligands A Fast Method for the aritisation of Hits Obtained from De Novo Design or 3D Database Search Programs. Journal of nputer-Aided Molecular Design 12 309-323. 

W, D J Willock, C R A Catlow, J M Thomas and G J Hutchings 1996. De Novo Design of icture-directing Agents for the Synthesis of Microporous Solids. Nature 382 604-606. 

Fig. 8. De novo designed a-hehcal proteins. Dimers of the amphiphilic helix-forming peptide a B, GELEELLKKLKELLKG (see Table 1), in which the nature of the linker connecting the individual heflces plays a critical role in the stmcture of the final protein, (a) Using a Pro residue as the linker, ie, a B-Pro-a B, three molecules aggregated to form a trimeric coded-cod. (b) Using Pro-Arg-Arg as the linker, ie, a B-Pro-Aig-Arg-a, resulted in the...

Fig. 9. A de novo designed P sheet protein, betabellin, formed by the dimerization of two identical four-stranded -sheets and a disulfide linking the two sheets. This model is for betabeUins 9 and later progenies the earher betabeUins contained a two-armed cross-linker connecting the sheets (51).

Flavin-containing Baeyer-Villiger monooxygenases (BVMOs) represent nature s equivalent of conventional peracids or de novo designed metal complexes... 

Rughani RV, Branco MC, Pochan D et al (2010) De novo design of a shear-thin recoverable peptide-based hydrogel capable of intrafibrillar photopolymerization. Macromolecules 43 7924-7930... 

Gunasekaran K, Ramakrishnan C, Balaram P (1997) Beta-hairpins in proteins revisited lessons for de novo design. Protein Eng 10 1131-1141... 

Pochan DJ, Schneider JP, Kretsinger J et al (2003) Thermally reversible hydrogels via intramolecular folding and consequent self- assembly of a de novo designed peptide. J Am Chem Soc 125 11802-11803... 

Methodologies for the de novo design and synthesis of polypeptides were recently developed. The preparation of periodic polypeptides, polypeptides containing artificial amino acids, polypeptides exhibiting rodlike structures, and hybrids of natural and artificial polypeptide segments was recently described [33],... 

The computational chemists were able to form collaborations with their fellow physical chemists. Some of the research questions dealt with molecular conformation and spectroscopy. The 1970s were full of small successes such as finding correlations between calculated and experimental properties. Some of these correlations were published. Even something so grand as the de novo design of a pharmaceutical was attempted but was somewhat beyond reach. 

As the availability of crystal structures increased in the early 1990s, a number of experimental and computational methods were developed to use the structure of the protein target as a route to discover novel hit compounds. The methods include de novo design, virtual screening, and fragment-based discovery. These developments are covered in more detail in the later chapters of this book, but their main features can be summarized as follows. 

Honma T. Recent advances in de novo design strategy for practical lead identification. Med Res Rev 2003 23 606-32. 

Bohm HJ. The computer program LUDI a new method for the de novo design of enzyme inhibitors. J Comput Aided Mol Design 1992 6 61-78. 

Honma T, Hayashi K, Aoyama T, Hashimoto N, Machida T, Fukasawa K, Iwama T, Ikeura C, Ikuta M, Suzuki-Takahashi I, Iwasawa Y, Hayama T, Nishimura S, Morishima H. Structure-based generation of a new class of potent Cdk4 inhibitors new de novo design strategy and library design. J Med Chem 2001 44 4615-27. 

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