Summary of - Avanafil mediated dual inhibition of IKKβ and TNFR1 in an experimental paradigm of Alzheimer’s disease: in silico and in vivo approach

Document Type

Article

Abstract

Study Background: The research titled “Avanafil mediated dual inhibition of IKKβ and TNFR1 in an experimental paradigm of Alzheimer’s disease: in silico and in vivo approach” discusses the effect of phosphodiesterase 5 inhibitor, avanafil in controlling neuroinflammation induced AD.

Research Goals and Hypotheses: The primary objective is to study the mechanism of action of phosphodiesterase 5 inhibitor, avanafil in inhibiting IKKβ and TNFR1 which plays a significant role in neuroinflammation.

Methodological Approach:

  1. Through in silico approach, the FDA-approved Zinc 15 library was docked with IKKB and TNFR1. The most promising compound exhibiting dual antagonistic effects on both IKKB and TNFR1 was chosen based on its bonding and non-bonding interactions. Subsequently, induced fit docking (IFD), molecular mechanics with generalized Born and surface area (MMGBSA), and molecular dynamics studies were performed and assessed.
  2. Lipopolysaccharide (LPS) administration led to cognitive decline in mice due to neuroinflammation. Avanafil was administered in two doses over 28 days, while LPS was given for 10 days. Behavioral assessments were conducted using the Morris water maze (MWM) and the passive avoidance test (PAT). Additionally, levels of inflammatory markers, oxidative stress indicators, amyloid beta (Ab), IKKB, and NF-kB in the brain were measured.

Results and Discoveries:

  1. Avanafil demonstrated strong binding affinity for IKKB and TNFR1. Molecular dynamics (MD) analysis predicted that avanafil maintains good stability with TNFR1 and IKKB.
  2. The 6 mg/kg dose of avanafil significantly enhanced performance in the Morris water maze (MWM), passive avoidance test (PAT), and oxidative stress parameters, while reducing amyloid beta (Ab) levels and inflammatory markers.

First Page-10659

Last Page- 10677

DOI- https://doi.org/10.1080/07391102.2022.2156924

Publication Year- 2023

Citation to the base paper:

Sivamaruthi, B. S., Raghani, N., Chorawala, M., Bhattacharya, S., Prajapati, B. G., Elossaily, G. M., & Chaiyasut, C. (2023). NF-κB Pathway and Its Inhibitors: A Promising Frontier in the Management of Alzheimer’s Disease. Biomedicines, 11(9), 2587.

Dorahy, G., Chen, J. Z., & Balle, T. (2023). Computer-aided drug design towards new psychotropic and neurological drugs. Molecules, 28(3), 1324.

Recommended Citation

Prasada Chowdari Gurram, Sairaj Satarker, Gautam Kumar, Farmiza Begum, Chetan Mehta, Usha Nayak, Jayesh Mudgal, Devinder Arora & Madhavan Nampoothiri(2023) Avanafil mediated dual inhibition of IKKβ and TNFR1 in an experimental paradigm of Alzheimer’s disease: in silico and in vivo approach, Journal of Biomolecular Structure and Dynamics, 41:20, 10659-10677, DOI: 10.1080/07391102.2022.2156924.

Publication Date

2023

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