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In Silico Development of Combinatorial Therapeutic Approaches Targeting Key Signaling Pathways in Metabolic Syndrome

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Abstract

Purpose

Dysregulations of key signaling pathways in metabolic syndrome are multifactorial, eventually leading to cardiovascular events. Hyperglycemia in conjunction with dyslipidemia induces insulin resistance and provokes release of proinflammatory cytokines resulting in chronic inflammation, accelerated lipid peroxidation with further development of atherosclerotic alterations and diabetes. We have proposed a novel combinatorial approach using FDA approved compounds targeting IL-17a and DPP4 to ameliorate a significant portion of the clustered clinical risks in patients with metabolic syndrome. In our current research we have modeled the outcomes of metabolic syndrome treatment using two distinct drug classes.

Methods

Targets were chosen based on the clustered clinical risks in metabolic syndrome: dyslipidemia, insulin resistance, impaired glucose control, and chronic inflammation. Drug development platform, BIOiSIM™, was used to narrow down two different drug classes with distinct modes of action and modalities. Pharmacokinetic and pharmacodynamic profiles of the most promising drugs were modeling showing predicted outcomes of combinatorial therapeutic interventions.

Results

Preliminary studies demonstrated that the most promising drugs belong to DPP-4 inhibitors and IL-17A inhibitors. Evogliptin was chosen to be a candidate for regulating glucose control with long term collateral benefit of weight loss and improved lipid profiles. Secukinumab, an IL-17A sequestering agent used in treating psoriasis, was selected as a repurposed candidate to address the sequential inflammatory disorders that follow the first metabolic insult.

Conclusions

Our analysis suggests this novel combinatorial therapeutic approach inducing DPP4 and Il-17a suppression has a high likelihood of ameliorating a significant portion of the clustered clinical risk in metabolic syndrome.

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Acknowledgments and Disclosures

The authors are all employees of Verisim Life and used a proprietary AI-driven platform to generate the outcomes for the manuscript.

All data generated or analyzed during this study are included in this published article

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  1. VeriSIM Life, 1 Sansome Street, Suite 3500, San Francisco, California, 94104, USA

    Maksim Khotimchenko, Nicholas E. Brunk, Mark S. Hixon, Daniel M. Walden, Hypatia Hou, Kaushik Chakravarty & Jyotika Varshney

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  1. Maksim Khotimchenko
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  2. Nicholas E. Brunk
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Correspondence to Kaushik Chakravarty or Jyotika Varshney.

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Khotimchenko, M., Brunk, N.E., Hixon, M.S. et al. In Silico Development of Combinatorial Therapeutic Approaches Targeting Key Signaling Pathways in Metabolic Syndrome. Pharm Res 39, 2937–2950 (2022). https://doi.org/10.1007/s11095-022-03231-z

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