In silico work flow for scaffold hopping in Leishmania

BMC Research Notes

Rahul Banerjee³  Nanda Ghoshal¹  Dhananjay Bhattacharyya²  Ambarnil Ghosh³  Barnali Waugh³ 

[1] Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India;Computer Science Division, Saha Institute of Nuclear Physics, Sector-1, Block AF, Biddhannagar, Kolkata 700064, India;Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, Sector - 1, Block – AF, Bidhannagar, Kolkata 700064, India

关键词: Scaffold hopping;    Pharamacophore;    Drug targets;    Leishmaniasis;   

Others  :  1125627
DOI  :  10.1186/1756-0500-7-802

 received in 2014-05-01, accepted in 2014-10-29,  发布年份 2014

【 摘 要 】

Background

Leishmaniasis,a broad spectrum of diseases caused by several sister species of protozoa belonging to family trypanosomatidae and genus leishmania , generally affects poorer sections of the populace in third world countries. With the emergence of strains resistant to traditional therapies and the high cost of second line drugs which generally have severe side effects, it becomes imperative to continue the search for alternative drugs to combat the disease. In this work, the leishmanial genomes and the human genome have been compared to identify proteins unique to the parasite and whose structures (or those of close homologues) are available in the Protein Data Bank. Subsequent to the prioritization of these proteins (based on their essentiality, virulence factor etc.), inhibitors have been identified for a subset of these prospective drug targets by means of an exhaustive literature survey. A set of three dimensional protein-ligand complexes have been assembled from the list of leishmanial drug targets by culling structures from the Protein Data Bank or by means of template based homology modeling followed by ligand docking with the GOLD software. Based on these complexes several structure based pharmacophores have been designed and used to search for alternative inhibitors in the ZINC database.

Result

This process led to a list of prospective compounds which could serve as potential antileishmanials. These small molecules were also used to search the Drug Bank to identify prospective lead compounds already in use as approved drugs. Interestingly, paromomycin which is currently being used as an antileishmanial drug spontaneously appeared in the list, probably giving added confidence to the ‘scaffold hopping’ computational procedures adopted in this work.

Conclusions

The report thus provides the basis to experimentally verify several lead compounds for their predicted antileishmanial activity and includes several useful data bases of prospective drug targets in leishmania, their inhibitors and protein – inhibitor three dimensional complexes.

【 授权许可】

   
2014 Waugh et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

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