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) [1]. 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) [2]. 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 in vivo [3], because this would favour more closely related sequences and should reduce problems caused by incompatible junctions. An integral generic program package is under development to model this process in silico. The heart of the program is a specially structured database that connects the biosynthetic order of synthase/synthetase enzymes to the sequences of the component polypeptides. The additional linkage to the gene sequences allows the integration of DNA sequence with product structure. The database contains sequences of the well-characterised PKS and NRPS clusters to act as building blocks for the production of novel products. It is easy to add custom sequences to the database. One function of the program is the ability to generate virtual recombinants between clusters. This can be done using a recombination model to predict sites for homologous recombination or by user defined recombination sites (e.g. to model in vitro genetic manipulation such as module replacement). The program predicts the chemical structure of the resulting products and allows them to be inserted into a virtual compound database for molecular modelling studies. An optional 'reverse Genetics' module analyses a given chemical structure to see if it could be produced by a PKS or NRPS synthesis cluster and suggests the DNA sequence of a suitable cluster based on building blocks derived from clusters contained in the data base. There are also component programs to recognise and annotate new gene clusters from microbial genome sequencing projects or in metagenomes of soil and/or marine microorganisms [4]. 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. [1] D. Hranueli, J. Cullum, B. Basrak, P. Goldstein, P.F. Long, Curr. Med. Chem. 12 (2005) 1697-1704. [2] K.J. Weissman, P.F. Leadlay, Nat. Rev. Microbiol. 3 (2005) 925-936. [3] C. Rayssiguier, D.S. Thaler, M. Radman, Nature 342 (1989) 396-401. [4] W.C. Dunlap, M. Jaspars, D. Hranueli, C.N. Battershill, N. Perić-Concha, J. Zucko, S.H. Wright, P.F. Long, Curr. Med. Chem., 13 (2006) 697-710.