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PyRod Enables Rational Homology Model-based Virtual Screening Against MCHR1.

ABSTRACT: Several encouraging pre-clinical results highlight the melanin-concentrating hormone receptor 1 (MCHR1) as promising target for anti-obesity drug development. Currently however, experimentally resolved structures of MCHR1 are not available, which complicates rational drug design campaigns. In this study, we aimed at developing accurate, homologymodel-based 3D pharmacophores against MCHR1. We show that traditional approaches involving docking of known active small molecules are hindered by the flexibility of binding pocket residues. Instead, we derived three-dimensional pharmacophores from molecular dynamics simulations by employing our novel open-source software PyRod. In a retrospective evaluation, the generated 3D pharmacophores were highly predictive returning up to 35?% of active molecules and showing an early enrichment (EF1) of up to 27.6. Furthermore, PyRod pharmacophores demonstrate higher sensitivity than ligand-based pharmacophores and deliver structural insights, which are key to rational lead optimization.

SUBMITTER: Schaller D

PROVIDER: S-EPMC7317519 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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PyRod Enables Rational Homology Model-based Virtual Screening Against MCHR1.

Schaller David D Wolber Gerhard G

Molecular informatics 20200429 6

Several encouraging pre-clinical results highlight the melanin-concentrating hormone receptor 1 (MCHR1) as promising target for anti-obesity drug development. Currently however, experimentally resolved structures of MCHR1 are not available, which complicates rational drug design campaigns. In this study, we aimed at developing accurate, homologymodel-based 3D pharmacophores against MCHR1. We show that traditional approaches involving docking of known active small molecules are hindered by the fl ...[more]

PMID: 32329245

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Project description:Schistosomiasis is a parasitic neglected disease with praziquantel (PZQ) utilized as the main drug for treatment, despite its low effectiveness against early stages of the worm. To aid in the search for new drugs to tackle schistosomiasis, computer-aided drug design has been proved a helpful tool to enhance the search and initial identification of schistosomicidal compounds, allowing fast and cost-efficient progress in drug discovery. The combination of high-throughput in silico data followed by in vitro phenotypic screening assays allows the assessment of a vast library of compounds with the potential to inhibit a single or even several biological targets in a more time- and cost-saving manner. Here, we describe the molecular docking for in silico screening of predicted homology models of five protein kinases (JNK, p38, ERK1, ERK2, and FES) of Schistosoma mansoni against approximately 85,000 molecules from the Managed Chemical Compounds Collection (MCCC) of the University of Nottingham (UK). We selected 169 molecules predicted to bind to SmERK1, SmERK2, SmFES, SmJNK, and/or Smp38 for in vitro screening assays using schistosomula and adult worms. In total, 89 (52.6%) molecules were considered active in at least one of the assays. This approach shows a much higher efficiency when compared to using only traditional high-throughput in vitro screening assays, where initial positive hits are retrieved from testing thousands of molecules. Additionally, when we focused on compound promiscuity over selectivity, we were able to efficiently detect active compounds that are predicted to target all kinases at the same time. This approach reinforces the concept of polypharmacology aiming for "one drug-multiple targets". Moreover, at least 17 active compounds presented satisfactory drug-like properties score when compared to PZQ, which allows for optimization before further in vivo screening assays. In conclusion, our data support the use of computer-aided drug design methodologies in conjunction with high-throughput screening approach.

Dataset Information

PyRod Enables Rational Homology Model-based Virtual Screening Against MCHR1.

Publications

PyRod Enables Rational Homology Model-based Virtual Screening Against MCHR1.

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