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The first oral drug for the treatment of COVID-19, Paxlovid, has been authorized; however, nirmatrelvir, a major component of the drug, is reported to be associated with some side effects. Moreover, the appearance of many novel variants raises concerns about drug resistance, and designing new potent inhibitors to prevent viral replication is thus urgent. In this context, using a hybrid approach combining machine learning (ML) and free energy simulations, 6 compounds obtained by modifying nirmatrelvir were proposed to bind strongly to SARS-CoV-2 Mpro. The structural modification of nirmatrelvir significantly enhances the electrostatic interaction free energy between the protein and ligand and slightly decreases the vdW term. However, the vdW term is the most important factor in controlling the ligand-binding affinity. In addition, the modified nirmatrelvir might be less toxic to the human body than the original inhibitor., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Checkpoint kinase 1 (CHK1) is a serine/threonine-protein kinase that is involved in cell cycle regulation in eukaryotes. Inhibition of CHK1 is thus considered as a promising approach in cancer therapy. In this study, the fast pulling of ligand (FPL) process was applied to predict the relative binding affinities of CHK1 inhibitors using non-equilibrium molecular dynamics (MD) simulations. The work of external harmonic forces to pull the ligand out of the binding cavity strongly correlated with the experimental binding affinity of CHK1 inhibitors with the correlation coefficient of R = -0.88 and an overall root mean square error (RMSE) of 0.99 kcal/mol. The data indicate that the FPL method is highly accurate in predicting the relative binding free energies of CHK1 inhibitors with an affordable CPU time. A new set of molecules were designed based on the molecular modeling of interactions between the known inhibitor and CHK1 as inhibitory candidates. Molecular docking and FPL results exhibited that the binding affinities of developed ligands were similar to the known inhibitor in interaction with the catalytic site of CHK1, producing very potential CHK1 inhibitors of that the inhibitory activities should be further evaluated in vitro., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The residue E22 plays a critical role in the aggregation process of Amyloid beta (Aβ) peptides. The effect of E22Q mutant on the shapes of the solvated Aβ 11-40 trimer is clarified using a replica exchange molecular dynamics (REMD) simulation employing ∼20.6 μs of MD simulations with 48 disparate replicas. The increase of intramolecular polar contacts and salt bridge between the residue D23 to residues (24-29) was observed. The residual secondary structure of the mutated trimer is shifted in a similar way to the picture observed in previous investigations of F19W mutant. The free energy surface (FES) of the mutated E22Q system has a fewer number of minima in comparison with the wild-type trimer. The optimized shapes of the mutated E22Q form a significant increase in beta structure (47%) and serious decrease in coil content (46%) compared with the wild-type (of 36 and 56%, respectively). The binding affinity of constituting chains to the rest is of -43.7 ± 6.5 kcal/mol, implying that the representative structure of E22Q is more stable than the wild-type one. Furthermore, the E22Q mutant increases the size of stable structures due to larger collision cross section (CCS) and solvent accessible area (SASA). The observed results may enhance the Aβ inhibition throughout the contribution to the knowledge of the Aβ oligomerization/aggregation., (Copyright © 2018 Elsevier Inc. All rights reserved.)