Study on Structure Activity Relationship of Natural Flavonoids against Thrombin by Molecular Docking Virtual Screening Combined with Activity Evaluation In Vitro

Abstract

Thrombin, a key enzyme of the serine protease superfamily, plays an integral role in the blood coagulation cascade and thrombotic diseases. In view of this, it is worthwhile to establish a method to screen thrombin inhibitors (such as natural flavonoid-type inhibitors) as well as investigate their structure activity relationships. Virtual screening using molecular docking technique was used to screen 103 flavonoids. Out of this number, 42 target compounds were selected, and their inhibitory effects on thrombin assayed by chromogenic substrate method. The results indicated that the carbon-carbon double bond group at the C2, C3 sites and the carbonyl group at the C4 sites of flavones were essential for thrombin inhibition, whereas the methoxy and O-glycosyl groups reduced thrombin inhibition. Noteworthy, introduction of OH groups at different positions on flavonoids either decreased or increased anti-thrombin potential. Myricetin exhibited the highest inhibitory potential against thrombin with an IC50 value of 56 μM. Purposively, the established molecular docking virtual screening method is not limited to exploring flavonoid structure activity relationships to anti-thrombin activity but also usefully discovering other natural active constituents.

Complexity of active medicinal ingredients in radix scutellariae with sodium hydrosulfite exposure

“…It has been proven that the number of hydroxyl groups on the B ring directly impacts the activity, which is also markedly enhanced when a double bond is introduced into the C ring [ 22 ]. The hydroxyl group at positions C-5 and C-7 together in the A ring, as well as the C-3', C-4' and C-5' sites on the B ring, can all increase the activities obviously [ 23 , 24 ]. A hydroxyl group can also be located in another position, such as C-6 [ 25 ].…”

“…bond is introduced into the C ring [22]. The hydroxyl group at positions C-5 and C-7 together in the A ring, as well as the C-3', C-4' and C-5' sites on the B ring, can all increase the activities obviously [23,24]. A hydroxyl group can also be located in another position, such as C-6 [25].…”

“…A hydroxyl group can also be located in another position, such as C-6 [25]. It has been proven that baicalein is 2~5 times more antibiotically active than baicalin and 1~3 times better than baicalin at inhibiting IL-1β and converting enzymes [24]. Second, except for baicalin and wogonoside, the other flavonoids were free flavonoids without sugar moieties.…”

Flavonoids: A complementary approach to conventional therapy of COVID-19?

“…In a number of studies molecular docking technology was used for screening purposes. Despite the valuable use of this method to rapidly discover novel inhibitors of SARS-CoV-2, there are some disadvantages which include low accuracy and high rate of false-positive results (Wang et al 2020 ). However, compounds which are identified through such virtual screening methods can be further examined in high-throughput enzymatic in-vitro assays, followed by more in-depth in vivo investigations, such as studies on efficacy and toxicity.…”

ANÁLISIS BIOQUÍMICO DE DOS FRACCIONES CON ACCIÓN ANTICOAGULANTE DE LAS HOJAS DE Oenothera rosea “CHUPASANGRE”

“…Recientemente, han reportado ensayos con 42 flavonoides para evaluar el efecto sobre la trombina, utilizando el sustrato cromogénico S-2238; sus resultados indican que algunos flavonoides mostraron fuerte efecto inhibitorio, IC50, con valores desde 56,50 μM a 99,70 μM, estos son miricetina, scutellareína, isorhamnetina, miricitrina, baicalina, apigenina e hidroxigenkwanina 9 .…”