Adequate prediction for inhibitor affinity of Aβ₄₀protofibril using the linear interaction energy method

Abstract

The efficient approach to estimate inhibitors targeting Aβ oligomers and fibrils is an important issue in Alzheimer's disease treatment.

Estimating the ligand‐binding affinity via λ‐dependent umbrella sampling simulations

“…[9,10] In these problems, researcher would choose an appropriate method to evaluate the binding affinity of an inhibitor to an enzyme according to their demands due to the accuracy and precision of an approach is normally depended on the required central processing unit (CPU) time consumption. [11][12][13][14][15][16] Estimations of the ligand-binding free energies are probably performed according to Scheme 1. [16] In particular, a rapid protocol is generally engaged to rank the ligand-binding affinity of several thousand to million compounds.…”

Effective estimation of the inhibitor affinity of HIV-1 proteaseviaa modified LIE approach

“…However, the computing resource cost would be signicantly lower than that required for the MM-PBSA or FEP methods. 89 Obtaining an efficient scheme for rapidly and accurately estimating the ligand-binding affinity to the HIV-1 PR system is of great attraction. The proposed LIE model would enhance the development of HIV therapy.…”

“…The ligand was put into a periodic boundary dodecahedron box with a volume of $74 nm 3 and consists of 1 inhibitor molecule and 2400 water molecules (a total $7200 atoms). The simulation was carried out with parameters referring to the previous work, 26,89 in which the non-bonded pair cut-off is 1.0 nm. The vdW cut-off is 1.0 nm and the PME method is used for electrostatic interactions.…”

“…[95][96][97][98][99] Recent work on amyloid beta-peptide system conrmed that the coefficients are a ¼ 0.288 and b ¼ 0.049. 89 The use of these coefficients to determine the binding free energy of HIV-1 PR + inhibitor produces a failure since the correlation coefficients are observed as R ¼ 0.20, 0.14, and À0.43 corresponding to the set of empirical parameters of (0.180, 0.500), (0.180, 0.300), and (0.288, 0.049), respectively. Overall, the empirical coefficients are changed depending on the applied receptors.…”

“…The estimation of ligand-binding affinity via the LIE scheme was indicated that it is required less computing resources than other end-point approaches such as MM-PBSA or FEP methods. 89 In fact, in the LIE model, it was not necessary to perform additional computations to calculate the difference in the binding free energy alongside the production MD simulations. All of the free energy terms required to determine the binding free energy can be analyzed via the recorded conformations of the solvated complexes and the isolated ligands in the solution.…”