Unraveling the Mechanism of Platelet Aggregation Suppression by Monoterpenoids

Liliya E Nikitina,Larisa L Frolova,Ilmir R Gilfanov,Airat R Kayumov,Natalia S Andriutsa,Elena V Antina,Ilfat Z Rakhmatullin,Olga V Ostolopovskaya,Zulfiya R Azizova,Mohammed A Khelkhal,Sergei V Kiselev,Alexander V Kutchin,Aigul R Galembikova,Ayzira F Timerova,Pavel S Bocharov,Vladimir V Klochkov,Alexander A Ksenofontov,Roman S Pavelyev,Sergei V Boichuk

doi:10.3390/bioengineering9010024

Abstract

Platelet aggregation causes various diseases and therefore challenges the development of novel antiaggregatory drugs. In this study, we report the possible mechanism of platelet aggregation suppression by newly synthesized myrtenol-derived monoterpenoids carrying different heteroatoms (sulphur, oxygen, or nitrogen). Despite all tested compounds suppressed the platelet aggregation in vitro, the most significant effect was observed for the S-containing compounds. The molecular docking confirmed the putative interaction of all tested compounds with the platelet’s P2Y12 receptor suggesting that the anti-aggregation properties of monoterpenoids are implemented by blocking the P2Y12 function. The calculated binding force depended on heteroatom in monoterpenoids and significantly decreased with the exchanging of the sulphur atom with oxygen or nitrogen. On the other hand, in NMR studies on dodecyl phosphocholine (DPC) as a membrane model, only S-containing compound was found to be bound with DPC micelles surface. Meanwhile, no stable complexes between DPC micelles with either O- or N-containing compounds were observed. The binding of S-containing compound with cellular membrane reinforces the mechanical properties of the latter, thereby preventing its destabilization and subsequent clot formation on the phospholipid surface. Taken together, our data demonstrate that S-containing myrtenol-derived monoterpenoid suppresses the platelet aggregation in vitro via both membrane stabilization and blocking the P2Y12 receptor and, thus, appears as a promising agent for hemostasis control.

Highlights

The abnormal changes in blood coagulation leading to hemostasis disorders are the key elements of various obstetric and surgical pathology, cardiovascular, cerebrovascular, infectious, and immune diseases [1,2,3,4]
Compounds 2–5 were synthesized based on (+)—myrtenol 1, which was prepared by the oxidation of (+) α-pinene with tert-butyl hydroperoxide in the presence of catalytic amounts of SeO2 according to a well-known procedure [22]
Since the aggregation induction by adenosine diphosphate (ADP) and other effectors was significantly suppressed in presence of monoterpenoids, we suggested their interaction with the P2Y12 receptor

Summary

Introduction

The abnormal changes in blood coagulation leading to hemostasis disorders are the key elements of various obstetric and surgical pathology, cardiovascular, cerebrovascular, infectious, and immune diseases [1,2,3,4]. The prevention and treatment of thrombosis and hemorrhagic conditions remain challenging and require a deeper insight into molecular mechanisms of blood coagulation and its regulation. It is worthwhile noting that most of the drugs suppressing the activity of platelets available to date do not guarantee effective prevention or treatment of thrombosis. The resistance of up to 61% of patients has been reported to aspirin, the most common and widely used anti-aggregation agent, which acts as an irreversible blocker of the cyclooxygenase enzymes and thromboxane A2 synthesis inhibitor [5]. The clopidogrel resistance, an inhibitor of well-known platelet receptors P2Y12 , was reported to be in a range of 5–45% [6]. The development of new agents for corrections of the hemostasis system disorders is strictly required

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