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. 2023 May 15;13(5):658.
doi: 10.3390/metabo13050658.

Computational Insights into Natural Antischistosomal Metabolites as SmHDAC8 Inhibitors: Molecular Docking, ADMET Profiling, and Molecular Dynamics Simulation

Abdulrahim A Alzain  1 , Rua M Mukhtar  1 , Nihal Abdelmoniem  1 , Fatima A Elbadwi  1 , Amira Hussien  2 , Elrashied A E Garelnabi  3 , Wadah Osman  4   5 , Asmaa E Sherif  4   6 , Amgad I M Khedr  7 , Kholoud F Ghazawi  8 , Waad A Samman  9 , Sabrin R M Ibrahim  10   11 , Gamal A Mohamed  12 , Ahmed Ashour  4   6
Affiliations

Computational Insights into Natural Antischistosomal Metabolites as SmHDAC8 Inhibitors: Molecular Docking, ADMET Profiling, and Molecular Dynamics Simulation

Abdulrahim A Alzain et al. Metabolites. .

Abstract

Schistosomiasis is a neglected tropical disease with a significant socioeconomic impact. It is caused by several species of blood trematodes from the genus Schistosoma, with S. mansoni being the most prevalent. Praziquantel (PZQ) is the only drug available for treatment, but it is vulnerable to drug resistance and ineffective in the juvenile stage. Therefore, identifying new treatments is crucial. SmHDAC8 is a promising therapeutic target, and a new allosteric site was discovered, providing the opportunity for the identification of a new class of inhibitors. In this study, molecular docking was used to screen 13,257 phytochemicals from 80 Saudi medicinal plants for inhibitory activity on the SmHDAC8 allosteric site. Nine compounds with better docking scores than the reference were identified, and four of them (LTS0233470, LTS0020703, LTS0033093, and LTS0028823) exhibited promising results in ADMET analysis and molecular dynamics simulation. These compounds should be further explored experimentally as potential allosteric inhibitors of SmHDAC8.

Keywords: SmHDAC8; allosteric; drug discovery; health and wellbeing; molecular docking; molecular dynamics; phytochemicals; schistosomiasis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The overall workflow of the study.
Figure 2
Figure 2
The 2D and 3D diagram of the top compounds with the SmHDAC8 (PDB ID: 7P2U). (A) Compound 1, (B) compound 2, (C) compound 3, and (D) compound 4.
Figure 2
Figure 2
The 2D and 3D diagram of the top compounds with the SmHDAC8 (PDB ID: 7P2U). (A) Compound 1, (B) compound 2, (C) compound 3, and (D) compound 4.
Figure 3
Figure 3
RMSD plots of the top compounds and the reference with the SmHDAC8 (PDB ID: 7P2U) during 100 ns molecular dynamics simulation. (A) compound 1, (B) compound 2, (C) compound 3, (D) compound 4, and (E) reference.
Figure 4
Figure 4
RMSF plots of the top compounds and the reference with the SmHDAC8 (PDB ID: 7P2U) during 100 ns molecular dynamics simulation. (A) Compound 1, (B) compound 2, (C) compound 3, (D) compound 4, and (E) reference. Protein residues that interact with the ligand are marked with green-colored vertical bars.
Figure 5
Figure 5
Interactions of the top compounds and the reference with the SmHDAC8 (PDB ID: 7P2U) during 100 ns molecular dynamics simulation. (A) Compound 1, (B) compound 2, (C) compound 3, (D) compound 4, and (E) reference.
See this image and copyright information in PMC

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