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Identification of Leishmania donovani Topoisomerase 1 inhibitors via intuitive scaffold hopping and bioisosteric modification of known Top 1 inhibitors.

ABSTRACT: A library of arylidenefuropyridinediones was discovered as potent inhibitors of Leishmania donovani Topoisomerase 1 (LdTop1) where the active molecules displayed considerable inhibition with single digit micromolar EC50 values. This molecular library was designed via intuitive scaffold hopping and bioisosteric modification of known topoisomerase 1 inhibitors such as camptothecin, edotecarin and etc. The design was rationalized by molecular docking analysis of the compound prototype with human topoisomerase 1 (HTop1) and Leishmania donovani topoisomerase 1(LdTop1). The most active compound 4 displayed no cytotoxicity against normal mammalian COS7 cell line (~100 fold less inhibition at the EC50). Similar to camptothecin, 4 interacted with free LdTop1 as observed in the preincubation DNA relaxation inhibition experiment. It also displayed anti-protozoal activity against Leishmania donovani promastigote. Crystal structure investigation of 4 and its molecular modelling with LdTop1 revealed putative binding sites in the enzyme that could be harnessed to generate molecules with better potency.

SUBMITTER: Mamidala R

PROVIDER: S-EPMC4879574 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Identification of Leishmania donovani Topoisomerase 1 inhibitors via intuitive scaffold hopping and bioisosteric modification of known Top 1 inhibitors.

Mamidala Rajinikanth R Majumdar Papiya P Jha Kunal Kumar KK Bathula Chandramohan C Agarwal Rahul R Chary M Thirumala MT Majumder Hemanta K HK Munshi Parthapratim P Sen Subhabrata S

Scientific reports 20160525

A library of arylidenefuropyridinediones was discovered as potent inhibitors of Leishmania donovani Topoisomerase 1 (LdTop1) where the active molecules displayed considerable inhibition with single digit micromolar EC50 values. This molecular library was designed via intuitive scaffold hopping and bioisosteric modification of known topoisomerase 1 inhibitors such as camptothecin, edotecarin and etc. The design was rationalized by molecular docking analysis of the compound prototype with human to ...[more]

PMID: 27221589

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Project description:BackgroundLeishmaniasis,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.ResultThis 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.ConclusionsThe 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.

Dataset Information

Identification of Leishmania donovani Topoisomerase 1 inhibitors via intuitive scaffold hopping and bioisosteric modification of known Top 1 inhibitors.

Publications

Identification of Leishmania donovani Topoisomerase 1 inhibitors via intuitive scaffold hopping and bioisosteric modification of known Top 1 inhibitors.

Similar Datasets

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