Prediction of AChE-ligand affinity using the umbrella sampling simulation

• Published in: Journal of molecular graphics & modelling 2019-12, Vol.93, p.107441, Article 107441
• Main Authors: Lan, Ngo Thi, Vu, Khanh B., Dao Ngoc, Minh Khue, Tran, Phuong-Thao, Hiep, Dinh Minh, Tung, Nguyen Thanh, Ngo, Son Tung
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; ADME; Binding affinity; Cordyceps; Docking; Umbrella sampling
• ISSN: 1093-3263; 1873-4243
• DOI: 10.1016/j.jmgm.2019.107441

Acetylcholinesterase (AChE) is characterized as a key target for designing inhibitors to prevent Alzheimer's disease (AD). The binding free energy of a ligand to the AChE enzyme is a critical factor to screen the potential inhibitor in addition to pharmacokinetics and pharmacology estimation. The biased sampling or umbrella sampling (US) method emerges as a reliable technique to estimate the AChE-inhibitor affinity. The affinity is computed as the difference between the largest and smallest values of the free energy change, obtained by using a potential of mean force (PMF) analysis. The obtained affinities overestimate the experimental ones with a value of ∼4.10 kcal/mol. However, a very good correlation coefficient (R=0.94) between the computational and experimental values is observed. Consequently, the obtained precision is high since the mean error of the free energy value is of δ=1.17 kcal/mol. The binding affinity of a new ligand can be consistently appraised via the US technique. Therefore, the absolute binding free energy of a ligand to the AChE protein can be obtained via the linear regression with the root-mean-square errors (RMSE) of 0.98 kcal/mol. The small value of RMSE implies that ligands revealing the similar binding affinities are able to be discriminated through the US simulations. In addition, the derivatives of Cordyceps were recently reported that they are able to inhibit the AChE enzyme, resulting in an improvement in learning and cognitive ability for curing AD. The active metabolites of Cordyceps were thus evaluated as the potential inhibitors for the AChE enzyme, and the 5-Carboxy-2′-deoxyuridine compound can inhibit the activity of the AChE enzyme. These compounds are also passed the testing of Lipinski's rule of five, toxicity, crossing blood-brain barrier (BBB) ability, and human intestinal absorption. [Display omitted] •Accurate and precise evaluation of the AChE-ligand binding affinity via the umbrella sampling.•The obtained affinities overestimate the experiments by 4.10 kcal/mol.•The trial ligand-binding affinity can be obtained with the RMSE of 0.98 kcal/mol.•The 5-Carboxy-2′-deoxyuridine compound can inhibit the activity of the AChE enzyme.