Crystallographic mining of ASK1 regulators to unravel the intricate PPI interfaces for the discovery of small molecule

Agrahari, Ashish Kumar; Dikshit, Madhu; Asthana, Shailendra

doi:10.1016/j.csbj.2022.07.008

Cited by 7 publications

(14 citation statements)

References 226 publications

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“…Nevertheless, no medicine that has the ability to reverse NASH brosis is currently on the market, and the ones that have been made have not shown a promising effect 4 . Selonsertib has failed despite its great e cacy in inhibiting ASK1 since it speci cally targets the enzyme's catalytic region and totally shuts off ASK1 activity 4 . The complete inhibition of ASK1 will even interfere with its typical physiological function, which may be the cause of seleonsertib's adverse effects 4 .…”

Section: Introductionmentioning

confidence: 99%

“…Selonsertib has failed despite its great e cacy in inhibiting ASK1 since it speci cally targets the enzyme's catalytic region and totally shuts off ASK1 activity 4 . The complete inhibition of ASK1 will even interfere with its typical physiological function, which may be the cause of seleonsertib's adverse effects 4 . Hence, there is an unmet need for an alternate approach that might modulate ASK1 activity rather than totally blocking it, as well as minimize the adverse effect.…”

Section: Introductionmentioning

confidence: 99%

“…Several PPI modulators have already entered clinical research and have received marketing approval 5,6 2021; [7][8][9][10] . We have previously curated the most important positive and negative regulators of ASK1, and among them, we have chosen to investigate 14-3-3, a negative regulator of ASK1 4 .…”

Section: Introductionmentioning

confidence: 99%

“…The study also found that pASK1's kinase domain interacts with 14-3-3 in close proximity to its active site, suggesting that this association may restrict accessibility to the active site and/or alter its conformation 11 . The role of 14-3-3 as a negative regulator of ASK1 is well documented in the literature 4 ; However, the dynamics coupled atomistic mechanism by which 14-3-3 inhibits ASK1 activity has not been explored. In this study, we aim to investigate the molecular behavior of the 14-3-3 and ASK1 interfaces using molecular modeling and microsecond molecular dynamics simulations.…”

Section: Introductionmentioning

confidence: 99%

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Elucidation of Molecular Mechanisms of ASK1 Regulation by 14-3-3 for NASH therapeutics: Insights from Computational Simulations

Sarmadhikari

Asthana

Agrahari

2023

Preprint

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Nonalcoholic steatohepatitis (NASH) is a global health concern with no effective treatment options. Apoptosis-signaling kinase 1 (ASK1) hyperactivity induced by oxidative stress has been identified as a key contributor to hepatic inflammation, apoptosis, and liver fibrogenesis, is the hallmark of NASH. Several attempts by companies and academia have attempted to develop ASK1 inhibitors, however, they failed in clinical trials due to substantial side effects. Hence, there is an unmet need for an alternate approach such as protein-protein interactions (PPIs) to modulate ASK1 activity via allosteric regulators rather than complete blockage of ASK1. The PPI driven allosteric inhibition of ASK1 traverses a promising strategy as its regulators in disease states are well documented. Among them, 14-3-3, a -ve regulator that allosterically inhibits ASK1 as it restricts the access of the catalytic site by preventing the substrate from entering into the catalytic site, however the mechanistic insights have not been explored. The 14-3-3 binding site and its impact at catalysis site is wired through an unstructured region indicating the possibility that this process is highly dynamics coupled, a major bottleneck in PPI-based inhibitor designing. Therefore, we are investigating the structural behavior of 14-3-3 and ASK1 interfaces using molecular modeling and microsecond molecular dynamics simulations. We identified that dynamics which correlate the structural and functional implications of the allosteric modulation via 14-3-3 on ASK1’s catalytic site and underscores a novel strategy for allosteric inhibition of ASK1. Extensive molecular dynamics simulations revealed that the complex state of ASK1 (with 14-3-3) was more stable than the apo state with a more restricted catalytic pocket volume as it visualizes that it potentially prevents the substrate entry in the absence of a ligand. Our findings provide structural determinants of allosteric regulation of ASK1 by 14-3-3 for the development of novel therapeutics against ASK1.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Elucidation of Molecular Mechanisms of ASK1 Regulation by 14-3-3 for NASH therapeutics: Insights from Computational Simulations

Sarmadhikari

Asthana

Agrahari

2023

Preprint

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“…ASK1 appears to control several aspects of cellular signaling as it has over 90 potential protein interacting partners [ 5 ]. ASK1 is a key player in cellular stress response to a multitude of stimuli in a variety of cell types [ 6 , 7 , 8 , 9 ]. Perhaps the best-characterized role for ASK1 involves toll-like receptor (TLR) engagement of a pathogen-associated molecular pattern (PAMP), reactive oxygen species (ROS) generation, and activation of downstream transcription factors that lead to proinflammatory cytokine production.…”

Section: Introductionmentioning

confidence: 99%

The Function of ASK1 in Sepsis and Stress-Induced Disorders

Kostyak,

McKenzie,

Naik

2023

IJMS

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Apoptosis signal-regulating kinase 1 (ASK1) is a serine-threonine kinase that is ubiquitously expressed in nucleated cells and is responsible for the activation of multiple mitogen-activated protein kinases (MAPK) to regulate cell stress. Activation of ASK1 via cellular stress leads to activation of downstream signaling components, activation of transcription factors, and proinflammatory cytokine production. ASK1 is also expressed in anucleate platelets and is a key player in platelet activation as it is important for signaling. Interestingly, the mechanism of ASK1 activation is cell type-dependent. In this review we will explore how ASK1 regulates a variety of cellular processes from innate immune function to thrombosis and hemostasis. We will discuss how ASK1 influences FcγRIIA-mediated platelet reactivity and how that reactivity drives platelet clearance. Furthermore, we will explore the role of ASK1 in thromboxane (TxA2) generation, which highlights differences in the way ASK1 functions in mouse and human platelets.

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LOXL2 in non‐alcoholic Steatohepatitis (NASH): Insights into fibrosis pathogenesis and therapeutic potential

Immanuel,

Kumar,

Agrahari

et al. 2024

Liver International Communications

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Liver fibrosis involves increased extracellular matrix (ECM) deposition, with lysyl oxidase‐like 2 (LOXL2) emerging as a key player due to its upregulation in fibrotic tissue. As a member of the lysyl oxidase protein family, LOXL2 contributes to ECM accumulation and remodelling through fibre cross‐linking. Its aberrant expression in non‐alcoholic steatohepatitis (NASH) implicates it in liver fibrosis. LOXL2 promotes fibrosis by activating hepatic stellate cells, cross‐linking ECM proteins, and influencing oxidative stress, inflammation and lipid metabolism. Preclinical studies on LOXL2 inhibitors show promise in reducing fibrosis and improving liver function. Ongoing clinical trials further highlight LOXL2 as a potential anti‐fibrotic target. However, challenges such as species differences, tissue‐specific effects and the complexity of NASH pathogenesis require additional research. Understanding LOXL2's role in NASH will aid in developing effective treatments for NASH‐related fibrosis and liver damage.

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Crystallographic mining of ASK1 regulators to unravel the intricate PPI interfaces for the discovery of small molecule

Cited by 7 publications

References 226 publications

Elucidation of Molecular Mechanisms of ASK1 Regulation by 14-3-3 for NASH therapeutics: Insights from Computational Simulations

Elucidation of Molecular Mechanisms of ASK1 Regulation by 14-3-3 for NASH therapeutics: Insights from Computational Simulations

The Function of ASK1 in Sepsis and Stress-Induced Disorders

LOXL2 in non‐alcoholic Steatohepatitis (NASH): Insights into fibrosis pathogenesis and therapeutic potential

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