Effect of guggulsterone, a sterol identified in Commiphora gileadensis (Becham), on the dengue virus enzymes: Pharmacokinetics, molecular docking and molecular dynamics simulations studies

Objectives: Dengue infection is a serious public health problem in several regions of the world due to the lack of effective , appropriate therapy mainly for severe infection. Therefore, the development of agents with inhibitory properties targeting the dengue virus (DNV) replication is of utmost significance.Methods: Guggulsterone, a sterol reported in a local medicinal tree, Commiphora gileadensis, was investi-gated in silico for its inhibitory potency of dengue virus. Interaction between this guggulsterone and NS5 RNA dependent RNA polymerase, dengue methyltransferase, NS3 protease-helicase , dengue virus type 2 envelope glycoprotein were determined using molecular docking and molecular dynamics simu-lations study. Guggulsterone's ADME and toxicity were predicted in silico as well.Results: Our data revealed that guggulsterone has the lowest docking energy (-5.5 kcal/mol) with den-gue NS5 RNA-dependent RNA polymerase. While the interaction of guggulsterone with dengue virus type 2 envelope glycoprotein exhibited the highest docking energy (-3.4 kcal/mol), and was the most stable complex during molecular dynamic simulation. Guggulsterone was predicted to be a probable inhibitor of dengue virus type 2 envelope glycoprotein. ADME prediction showed no violation of Lipinski and Veber rules of guggulsterone. The tested compound may inhibit CYP2C19 and CYP2C9 and cannot inhibit CYP1A2, CYP2D6, and CYP3A4. Guggulsterone was shown to have no hepatotoxicity, cytotoxicity, or mutagenicity effect.Conclusions: It can be concluded from this study that guggulsterone may be applied as a natural com-pound for the prevention or treatment of dengue infections. More in vitro and in vivo testing is needed to validate the effectiveness of this natural compound.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).