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.
Breast cancer is the most substantial cancer among women in the world. The uncontrollably high DNA Methyltransferase-1 (DNMT1) activity which leads to abnormal gene expression is one of the primary cause of breast cancer. Therefore, DNMT1, as an essential enzyme in epigenetic regulation, is considered as a potential therapeutic target for breast cancer treatment. In this research, the inhibitors of DNMT1 were designed through fragment-based drug design. About 168,646 natural products from PubChem database were used as fragment candidates. Initial screening based on toxicity and Lipinski's Rule of Three was performed to obtain 2,601 favorable fragments. Pharmacophore-based rigid and flexible molecular docking simulation was employed with DNMT1 as the target protein. The selected fragments from docking simulation underwent fragment linking modification and second toxicity screening, generating 23 ligands. Subsequently, the newly designed ligands were subjected to pharmacophore-based flexible molecular docking simulation. Two ligands, HAMI 9 and HAMI 14, with Gibbs free binding energy of -11.6095 and -11.5904 kcal/mol, respectively, are considered as a promising inhibitor of DNMT1. The pharmacological properties of the ligands were analyzed using DataWarrior v04.07.02, Toxtree v2.6.13, SwissADME, admetSAR, and Molinspiration. The ligands show not only superior affinity and molecular interaction to DNMT1 but also have advantageous pharmacological properties compared to the standards. Additional in silico as well as in vivo experiments are needed to further assess the potency of HAMI 9 and HAMI 14 as drug candidates against breast cancer.
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