Pharmacophore-Based Virtual Screening Toward the Discovery of Novel Anti-echinococcal Compounds

Abstract

Echinococcosis is a serious helminthic zoonosis with a great impact on human health and livestock husbandry. However, the clinically used drugs (benzimidazoles) have a low cure rate, so alternative drugs are urgently needed. Currently, drug screenings for echinococcosis are mainly phenotype-based, and the efficiency of identifying active compounds is very low. With a pharmacophore model generated from the structures of active amino alcohols, we performed a virtual screening to discover novel compounds with anti-echinococcal activity. Sixty-two compounds from the virtual screening were tested on Echinococcus multilocularis protoscoleces, and 10 of these compounds were found to be active. After further evaluation of their cytotoxicity, S6 was selected along with two active amino alcohols for in vivo pharmacodynamic and pharmacokinetic studies. At the two tested doses (50 and 25 mg/kg), S6 inhibited the growth of E. multilocularis in mice (14.43 and 9.53%), but no significant difference between the treatment groups and control group was observed. Treatment with BTB4 and HT3 was shown to be ineffective. During the 28 days of treatment, the death of mice in the mebendazole, HT3, and BTB4 groups indicated their toxicity. The plasma concentration of S6 administered by both methods was very low, with the C max being only 1 ng/ml after oral administration and below the detection limit after intramuscular administration. In addition, the plasma concentrations of BTB4 and HT3 in vitro did not reach high enough levels to kill the parasites. The toxicities of these two amino alcohols indicated that they are not suitable for further development as anti-echinococcal drugs. However, further attempts should be made to increase the bioavailability of S6 and modify its structure. In this study, we demonstrate that pharmacophore-based virtual screenings with high drug identification efficiency could be used to find novel drugs for treating echinococcosis.

Ligand Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies of Asymmetrical Hexahydro-2H-Indazole Analogs of Curcumin (AIACs) to Discover Novel Estrogen Receptors Alpha (ERα) Inhibitor

“…), which was believed to show similar behavior. LBVS techniques that consist of substructure mining and fingerprint searches are faster than SBVS techniques (e.g., molecular docking) [22][23][24]. The benefit of combining docking primarily based digital screening with pharmacophore-primarily based digital screening is that the database of ligands can be pre-filtered by using a pharmacophore query, before assessment using docking simulations.…”

Glycogen Phosphorylase: A Drug Target of Amino Alcohols in Echinococcus granulosus, Predicted by a Computer-Aided Method

“…In addition, poor understanding of drug modes of action limits target-based drug screening and design in related studies. Recently, we focused on a series of amino alcohols (Liu et al, 2018;Liu et al, 2020) because MEF, which is used for the treatment of malaria and schistosomiasis, has recently been reported to be effective against Echinococcus spp. (Kuster et al, 2011;Liu et al, 2015;Rufener et al, 2018).…”

“…In our previous study, we reported a series of amino alcohols with potential effects on Echinococcus spp. (Liu et al, 2018;Liu et al, 2020). To predict the drug targets of these compounds, idTarget, a web server for inverse docking, was used in the current study.…”

A Pharmacophore-Based Approach to Demonstrating the Scope of Alcohol Dehydrogenases

“…Our strategy was analogous to building 3D Quantitative Structure Activity Relationship (QSAR) models in drug discovery. 17,36 By aligning low energy conformations of the tested substrates, then using their field properties to generate similarity scores and compare those to their reactivity in the NADH consumption assay, we aimed to generate a pharmacophore-based screening tool which could return an assessment of the likely reactivity of a substrate molecule naïve of the active site sequence. We adopted a pragmatic approach to the development of this tool, focussing on the key information needed by a prospecting synthetic chemist asking the question "will this substrate likely be reduced by (S)-ADH?…”

“…However, expanding the application of biocatalysis throughout drug discovery is timely, [17][18][19] as there is an increasing appreciation of the importance of 3D character and chirality in medicinal chemistry design, 20,21 with biocatalytic technologies becoming increasingly sophisticated. 2,13,[22][23][24][25][26] Such methods could provide ready access to enantioenriched building blocks.…”