Molecular Docking Studies of Royleanone Diterpenoids from Plectranthus spp. as P-Glycoprotein Inhibitors

Abstract

The development of multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. Several abietane diterpenes with antitumoral activities have been isolated from Plectranthus spp. such as 6,7-dehydroroyleanone (DHR, 1) and 7αacetoxy-6β-hydroxyroyleanone (AHR, 2). Several royleanone derivatives were prepared through hemi-synthesis from natural compounds 1 and 2, to achieve a small library of products with enhanced anti-P-glycoprotein activity. Nonetheless, some derivatives tend to be unstable. Therefore, in order to reasoning such lack of stability, the electron density based local reactivity descriptors condensed Fukui functions and dual descriptor were calculated for several derivatives of DHR. Additionally, molecular docking and molecular dynamics studies were performed on several other derivatives in order to clarify the molecular mechanisms by which they may exert their inhibitory effect in P-gp activity. The analysis on local reactivity descriptors was important to understand possible degradation pathways and to guide further synthetic approaches towards new royleanone derivatives. A molecular docking study suggested that the presence of aromatic moieties increases the binding affinity of royleanone derivatives towards P-gp. It further suggests that one royleanone benzoylated derivative may act as a non-competitive efflux modulator, when bound to the M-site. Future generation of novel royleanone derivatives will involve i) a selective modification of position C-12 with chemical moieties smaller than unsubstituted benzoyl rings and ii) the modification of the substitution pattern of the benzoyloxy moiety at position C-6.While cancer is one of the leading causes of death worldwide, 1 the development of multidrug resistance (MDR) is a major cause of failure in traditional cancer chemotherapy. 2 Development of MDR is often associated with mutations and/or overexpression of ABC (ATP-binding cassette) family of membrane transport proteins such as ABCB1, also known as

Royleanone Derivatives From Plectranthus spp. as a Novel Class of P-Glycoprotein Inhibitors

“…On the contrary, royleanones 1–4 showed the same efficacy in sensitive and MDR cancer cells implying that they could not be P-gp substrates. Moreover, Isca et al (2020) based on docking simulations also suggest that derivatives 4 and 23 act as non-competitive efflux inhibitors.…”

“…Based on the FAR (values above 1.50 indicate P-gp inhibition) and SI (values above 20 account for P-gp inhibition), we could see that only derivatives 4 and 23 have the ability to inhibit P-gp activity, with FAR values of 1.71 and 2.10, respectively, and SI of 21.60 and 26.50, respectively. Additionally, derivative 23 has shown a comparable inhibitory potential to the well-known P-gp inhibitor, Dexverapamil (FAR 2.13 and SI 26.90) ( Isca et al, 2020 ). A recent study used molecular docking and molecular dynamics to explore the interaction of derivatives 4 and 23 with P-gp and suggested that the presence of aromatic moieties increases the binding affinity of royleanone derivatives toward P-gp ( Isca et al, 2020 ).…”

“…Additionally, derivative 23 has shown a comparable inhibitory potential to the well-known P-gp inhibitor, Dexverapamil (FAR 2.13 and SI 26.90) ( Isca et al, 2020 ). A recent study used molecular docking and molecular dynamics to explore the interaction of derivatives 4 and 23 with P-gp and suggested that the presence of aromatic moieties increases the binding affinity of royleanone derivatives toward P-gp ( Isca et al, 2020 ). On the other hand, derivative 22 is also a benzoylated derivative, nonetheless, it does not show the ability to inhibit P-gp activity.…”

“…SI values above 20 account for P-gp inhibition. d Results published in Isca et al (2020) . Sensitive cancer cell line and its MDR counterpart used in the study: non-small cell lung carcinoma-NSCLC (NCI-H460 and NCI-H460/R).…”

“…The extraction and isolation process of 1 and 2 were performed according to Garcia et al (2018) and Bernardes et al (2018), respectively. Isca et al (2020).…”