Dataset Information

Genome-Targeted Drug Design: Understanding the Netropsin-DNA Interaction.

ABSTRACT: Knowledge of the sequence of the human genome has provided significant opportunities to exploit DNA as a target in the rational design of therapeutic agents. Among agents that target DNA, netropsin exhibits a strong preference for binding A/T rich regions. In order to investigate the key factors responsible for DNA recognition and binding by netropsin, molecular dynamics simulations were carried out on a DNA-netropsin complex in which two netropsin molecules are bound to each AATT site of the 16-mer d(CTTAATTCGAATTAAG)(2). In this complex, the two netropsins are bound to the DNA minor groove in a head-to-head orientation with the guanidinium-termini of both netropsins pointed toward the center of the DNA. Despite their identical environments, molecular dynamics simulations showed that the two netropsins exhibited differences in their respective RMS behaviors, binding energies, minor groove width fluctuations, and rotations of their structural planes. These observations suggest that DNA recognition and binding by small molecules may be governed by mechanism(s) that are much more complex than initially anticipated and may represent unexpected challenges in genome-targeted drug design.

SUBMITTER: Fang YY

PROVIDER: S-EPMC3032215 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Publications

Genome-Targeted Drug Design: Understanding the Netropsin-DNA Interaction.

Fang Ya-Yin YY Morris Vernon R VR Lingani Guy M GM Long Eric C EC Southerland William M WM

The open conference proceedings journal 20100101

Knowledge of the sequence of the human genome has provided significant opportunities to exploit DNA as a target in the rational design of therapeutic agents. Among agents that target DNA, netropsin exhibits a strong preference for binding A/T rich regions. In order to investigate the key factors responsible for DNA recognition and binding by netropsin, molecular dynamics simulations were carried out on a DNA-netropsin complex in which two netropsin molecules are bound to each AATT site of the 16 ...[more]

PMID: 21297883

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Project description:Since December 2019, the new SARS-CoV-2-related COVID-19 disease has caused a global pandemic and shut down the public life worldwide. Several proteins have emerged as potential therapeutic targets for drug development, and we sought out to review the commercially available and marketed SARS-CoV-2-targeted libraries ready for high-throughput virtual screening (HTVS). We evaluated the SARS-CoV-2-targeted, protease-inhibitor-focused and protein-protein-interaction-inhibitor-focused libraries to gain a better understanding of how these libraries were designed. The most common were ligand- and structure-based approaches, along with various filtering steps, using molecular descriptors. Often, these methods were combined to obtain the final library. We recognized the abundance of targeted libraries offered and complimented by the inclusion of analytical data; however, serious concerns had to be raised. Namely, vendors lack the information on the library design and the references to the primary literature. Few references to active compounds were also provided when using the ligand-based design and usually only protein classes or a general panel of targets were listed, along with a general reference to the methods, such as molecular docking for the structure-based design. No receptor data, docking protocols or even references to the applied molecular docking software (or other HTVS software), and no pharmacophore or filter design details were given. No detailed functional group or chemical space analyses were reported, and no specific orientation of the libraries toward the design of covalent or noncovalent inhibitors could be observed. All libraries contained pan-assay interference compounds (PAINS), rapid elimination of swill compounds (REOS) and aggregators, as well as focused on the drug-like model, with the majority of compounds possessing their molecular mass around 500 g/mol. These facts do not bode well for the use of the reviewed libraries in drug design and lend themselves to commercial drug companies to focus on and improve.

Dataset Information

Genome-Targeted Drug Design: Understanding the Netropsin-DNA Interaction.

Publications

Genome-Targeted Drug Design: Understanding the Netropsin-DNA Interaction.

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