We have located links that may give you full text access.
Mechanisms Contributing to Acquired Activated Protein C Resistance in Patients Treated with Thalidomide: A Molecular Dynamics Study.
Cardiovascular & Hematological Disorders Drug Targets 2023 January 24
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.
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.
Full text links
Related Resources
Trending Papers
Renin-Angiotensin-Aldosterone System: From History to Practice of a Secular Topic.International Journal of Molecular Sciences 2024 April 5
Albumin: a comprehensive review and practical guideline for clinical use.European Journal of Clinical Pharmacology 2024 April 13
Revascularization Strategy in Myocardial Infarction with Multivessel Disease.Journal of Clinical Medicine 2024 March 27
Clinical practice guidelines on the management of status epilepticus in adults: A systematic review.Epilepsia 2024 April 13
Interstitial Lung Disease: A Review.JAMA 2024 April 23
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.
By using this service, you agree to our terms of use and privacy policy.
Your Privacy Choices
You can now claim free CME credits for this literature searchClaim now
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app