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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Mechanisms Contributing to Acquired Activated Protein C Resistance in Patients Treated with Thalidomide: A Molecular
Correa Lara Maximiliano1,2, García Chavez Jaime1, Vega Lopez Armando2
1Homeostasis and Thrombosis Clinic, Centro Medico Nacional "La Raza", Instituto Mexicano del Seguro Social, Mexico City, Mexico.
Introduction:
There is a high incidence of venous thromboembolism (VTE) in patients with Multiple Myeloma (MM), however; until now, the exact mechanisms behind VTE in MM are unknown, and some of the elements that may play a significant role are the treatment with an immunomodulator (IMiD) and acquired resistance to activated protein C (APC).
Objective:
The study aims to reveal the possible mechanisms linked to the reduced antithrombotic activity of APC associated with thalidomide.
Methods:
The molecular docking approach was used to ascertain the in silico inhibitory potential of thalidomide on the APC protease domain in the architecture of the catalytic triad and its interaction with major substrate binding sites.
Results:
The coupling showed that the inhibitory activity of thalidomide depends on the induction of structural changes in the protease domain of APC, at the level of the Ser/His/Asp catalytic triad, as a result of a significant increase between the distances of CαAsp102 and Cα Ser195 (11.175 angstroms, increase 14.83%) and between CαSer195 and CαHis57 (9.478 angstroms, increase 13.78 %). This can result in an inefficient transfer of the proton between these residues, the other possible mechanism of inhibition, is a potential reduced binding of the substrate as a result of a direct interaction through a carbon-hydrogen bond on His57, an H-bond on Arg306, and a carbon hydrogen bond on Arg506.
Conclusion:
We demonstrate the in silico inhibitory potential of thalidomide on APC, through two possible inhibition mechanisms, a pathophysiologically relevant finding to understand the factors that can affect the stability and functions of APC in vivo.
Insights
Thalidomide may inhibit activated protein C (APC) by altering its structure and reducing substrate binding. This finding helps explain venous thromboembolism (VTE) in multiple myeloma (MM) patients treated with immunomodulators.
Area of Science:
- Biochemistry
- Hematology
- Pharmacology
Background:
- Multiple Myeloma (MM) patients exhibit a high incidence of venous thromboembolism (VTE).
- The precise mechanisms driving VTE in MM, particularly concerning immunomodulators (IMiDs) and activated protein C (APC) resistance, remain unclear.
Purpose of the Study:
- To investigate the potential mechanisms by which thalidomide reduces the antithrombotic activity of APC.
- To elucidate the molecular interactions between thalidomide and APC.
Main Methods:
- In silico molecular docking was employed to assess thalidomide's inhibitory potential on the APC protease domain.
- Analysis focused on interactions within the catalytic triad and substrate binding sites.
Main Results:
- Thalidomide induces structural changes in the APC protease domain, increasing distances within the Ser/His/Asp catalytic triad.
- These alterations may impair proton transfer, leading to inefficient APC function.
- Direct interactions, including hydrogen bonds, suggest reduced substrate binding by thalidomide.
Conclusions:
- Thalidomide demonstrates in silico inhibitory potential against APC through structural modification and substrate binding interference.
- These findings offer insights into APC dysfunction in MM patients treated with thalidomide, contributing to VTE risk understanding.
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