Screening of terpenoids as potential therapeutics against Zaire ebolavirus infection through pharmacophore-based drug design

Abstract

Backgroud: Ebola virus disease (EVD) has spread to various countries in the world and has caused many deaths. Five different virus species can cause EVD, but the most virulent is Zaire ebolavirus (EBOV). The genome of EBOV includes seven genes that encode proteins playing essential roles in the virus lifecycle. Among these proteins, VP24 plays a vital role in the inhibition of the host cells’ immune system. Therefore, VP24 is a potential target for EVD therapy. In the present study, a potential inhibitor of EBOV VP24 activity was identified through pharmacophore-based drug design. Methods: This research was a in silico study, using pharmacophore based molecular docking simulation to obtain inhibitor candidates. Result: Terpenoids were used as VP24 inhibitor candidates. In particular, 55,979 terpenoids were obtained from the PubChem database. An initial screening based on the toxicity prediction test was performed with DataWarrior software: 3,353 ligands were shown to have a favorable toxicity profile, but only 1,375 among them had suitable pharmacophore features. These ligands were used for pharmacophore-based rigid and flexible molecular docking simulations with PDB ID: 4M0Q, chosen as the crystal structure of EBOV VP24. Six ligands predicted to have strong molecular interactions with EBOV VP24 underwent pharmacological property analysis through various software packages, including DataWarrior, SwissADME, admetSAR, pkCSM, and Toxtree. Conclusions: Taxumairol V was identified as the best candidate for EVD drug therapy via EBOV VP24 inhibition based on its molecular properties, predicted molecular interactions with the target molecule, and predicted pharmacological properties.

Analogue discovery of safer alternatives to HCQ and CQ drugs for SAR-CoV-2 by computational design

“…The BBB is also positive, signifying that these compounds could enter the blood-brain barrier. CYPs play a vital role in the metabolism of drugs by catalyzing their biotransformation which is responsible for their degradation and excretion [ 52 ]; it is necessary to identify CYP-inhibiting properties during development of a new drug. Most of the analogues resulting from drug-likeness have low CYP450 inhibitory properties, except HCQ2, HCQ3, and CQ14 to CQ18 and CQ20 to CQ27.…”