engleski

System for the in silico generation of novel biologically active chemical entities

Modular polyketides and nonribosomal peptides are very important compounds for the pharmaceutical and agricultural industries. Their biosynthesis involves assembly of simple chemical building blocks into complex chemical structures by the catalytic activity of polyketide synthases (PKS) or nonribosomal peptide synthetases (NRPS). There has been a lot of interest in the last few years in generating new compounds for the production of novel drugs by manipulating the programming of such clusters in vitro (e.g. the idea of combinatorial biosynthesis). However, an important barrier to the progress is the fact that most changes made by in vitro methods result in very low yields or no detectable product. A possible solution to the yield problem would be the generation of novel clusters by homologous recombination system in vivo, because this would favour more closely related sequences and should reduce problems caused by incompatible junctions. An integral generic program package was developed to model this process in silico. This utilises a specially structured database, which links genetic structure to biosynthetic order, and contains a suite of computer programs to model the processes of the homologous recombination and predict the products of the recombinant clusters. There are also component programs to recognise and annotate new gene clusters from microbial genome sequencing projects or in gene-clusters present of the metagenomes of soil and/or marine microorganisms. The integral generic program package allows in silico generation of databases of novel chemical compounds that can be used for in silico screening using CDD technology.

Integral generic program package; in silico generation of novel chemical compounds; polyketides; nonribosomal peptides

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