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Identification of potent ROR? modulators: Scaffold variation.

ABSTRACT: We sought to develop ROR?-selective probe molecules in order to investigate the function of the receptor in vitro and in vivo and its role in the pathophysiology of disease. To accomplish this, we modified a potent dual ROR?/ROR? inverse agonist from the primary literature with the goal of improving selectivity for ROR? vs ROR?. Truncation of the Western portion of the molecule ablated activity at ROR? and led to a potent series of ROR? modulators. Continued exploration of this series investigated alternate replacement cores for the aminothiazole ring. Numerous suitable replacements were found during the course of our SAR investigations and are reported herein.

SUBMITTER: Doebelin C

PROVIDER: S-EPMC6238650 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Identification of potent RORβ modulators: Scaffold variation.

Doebelin Christelle C Patouret Rémi R Garcia-Ordonez Ruben D RD Chang Mi Ra MR Dharmarajan Venkatasubramanian V Novick Scott S Ciesla Anthony A Campbell Sean S Solt Laura A LA Griffin Patrick R PR Kamenecka Theodore M TM

Bioorganic & medicinal chemistry letters 20180816 19

We sought to develop RORβ-selective probe molecules in order to investigate the function of the receptor in vitro and in vivo and its role in the pathophysiology of disease. To accomplish this, we modified a potent dual RORβ/RORγ inverse agonist from the primary literature with the goal of improving selectivity for RORβ vs RORγ. Truncation of the Western portion of the molecule ablated activity at RORγ and led to a potent series of RORβ modulators. Continued exploration of this series investigat ...[more]

PMID: 30143422

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Project description:The current ongoing pandemic of COVID-19 urges immediate treatment measures for controlling the highly contagious SARS-CoV-2 infections. The papain-like protease (PLpro), which is released from nsp3, is presently being evaluated as a significant anti-viral drug target for COVID-19 therapy development. Particularly, PLpro is implicated in the cleavage of viral polyproteins and antagonizes the host innate immune response through its deubiquitinating and deISGylating actions, thus making it a high-profile antiviral therapeutic target. The present study reports a few specific food compounds that can bind tightly with the SARS-CoV-2 PLpro protein identified through extensive computational screening techniques. Precisely, extensive advanced computational approaches combining target-based virtual screening, particularly employing sub-structure based similarity search, molecular docking, molecular dynamics (MD) simulations, and MM-GBSA based binding free energy calculations have been employed for the identification of the most promising food compounds with substantial functional implications as SARS-CoV-2 PLpro protein inhibitors/modulators. Observations from the present research investigation also provide a deeper understanding of the binding modes of the proposed four food compounds with SARS-CoV-2 PLpro protein. In docking analyses, all compounds have established essential inter-molecular interaction profiles at the active site cavity of the SARS-CoV-2 PLpro protein. Similarly, the long-range 100 ns conventional MD simulation studies also provided an in-depth understanding of probable interactions and dynamic behaviour of the SARS-CoV-2 PLpro protein-food compound complexes. Binding free energies of all molecular systems revealed a strong interaction affinity of food compounds towards the SARS-CoV-2 PLpro protein. Moreover, clear-cut comparative analyses against the known standard inhibitor also suggest that proposed food compounds may act as potential active chemical entities for modulating the action of the SARS-CoV-2 PLpro protein.

Dataset Information

Identification of potent ROR? modulators: Scaffold variation.

Publications

Identification of potent RORβ modulators: Scaffold variation.

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