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Left-Hand Side Exploration of Novel Bacterial Topoisomerase Inhibitors to Improve Selectivity against hERG Binding.

ABSTRACT: Structure-activity relationship (SAR) exploration on the left-hand side (LHS) of a novel class of bacterial topoisomerase inhibitors led to a significant improvement in the selectivity against hERG cardiac channel binding with concomitant potent antimycobacterial activity. Bulky polar substituents at the C-7 position of the naphthyridone ring did not disturb its positioning between two base pairs of DNA. Further optimization of the polar substituents on the LHS of the naphthyridone ring led to potent antimycobacterial activity (Mtb MIC = 0.06 μM) against Mycobacterium tuberculosis (Mtb). Additionally, this knowledge provided a robust SAR understanding to mitigate the hERG risk. This compound class inhibits Mtb DNA gyrase and retains its antimycobacterial activity against moxifloxacin-resistant strains of Mtb. Finally, we demonstrate in vivo proof of concept in an acute mouse model of TB following oral administration of compound 19.

SUBMITTER: Hameed P S

PROVIDER: S-EPMC4499837 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Left-Hand Side Exploration of Novel Bacterial Topoisomerase Inhibitors to Improve Selectivity against hERG Binding.

Hameed P Shahul S Manjrekar Praveena P Raichurkar Anandkumar A Shinde Vikas V Puttur Jayashree J Shanbhag Gajanan G Chinnapattu Murugan M Patil Vikas V Rudrapatana Suresh S Sharma Sreevalli S Kumar C N Naveen CN Nandishaiah Radha R Madhavapeddi Prashanti P Sriram D D Solapure Suresh S Sambandamurthy Vasan K VK

ACS medicinal chemistry letters 20150522 7

Structure-activity relationship (SAR) exploration on the left-hand side (LHS) of a novel class of bacterial topoisomerase inhibitors led to a significant improvement in the selectivity against hERG cardiac channel binding with concomitant potent antimycobacterial activity. Bulky polar substituents at the C-7 position of the naphthyridone ring did not disturb its positioning between two base pairs of DNA. Further optimization of the polar substituents on the LHS of the naphthyridone ring led to p ...[more]

PMID: 26191359

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Project description:Cancer poses a substantial global health challenge, driving the need for innovative therapeutic solutions that offer improved effectiveness and fewer side effects. Topoisomerase I (Topo I) has emerged as a validated molecular target in the pursuit of developing anticancer drugs due to its critical role in DNA replication and transcription. (+)-Pancratistatin (PST), a naturally occurring compound found in various Amaryllidaceae plants, exhibits promising anticancer properties by inhibiting Topo I activity. However, its clinical utility is hindered by issues related to limited chemical availability and aqueous solubility. To address these challenges, molecular modelling techniques, including virtual screening, molecular docking, molecular mechanics with generalised born and surface area solvation (MM-GBSA) calculations, and molecular dynamics simulations were utilised to evaluate the binding interactions and energetics of PST analogues with Topo I, comparing them with the well-known Topo I inhibitor, Camptothecin. Among the compounds screened for this study, nitrogenated analogues emerged as the most encouraging drug candidates, exhibiting improved binding affinities, favourable interactions with the active site of Topo I, and stability of the protein-ligand complex. Structural analysis pinpointed key molecular determinants responsible for the heightened potency of nitrogenated analogues, shedding light on essential structural modifications for increased activity. Moreover, in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions highlighted favourable drug-like properties and reduced toxicity profiles for the most prominent nitrogenated analogues, further supporting their potential as effective anticancer agents. In summary, this screening study underscores the significance of nitrogenation in augmenting the anticancer efficacy of PST analogues targeting Topo I. The identified lead compounds exhibit significant potential for subsequent experimental validation and optimisation, thus facilitating the development of novel and efficacious anticancer therapeutics with enhanced pharmacological profiles.

Dataset Information

Left-Hand Side Exploration of Novel Bacterial Topoisomerase Inhibitors to Improve Selectivity against hERG Binding.

Publications

Left-Hand Side Exploration of Novel Bacterial Topoisomerase Inhibitors to Improve Selectivity against hERG Binding.

Similar Datasets

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