How accurate can molecular dynamics/linear response and Poisson-Boltzmann/solvent accessible surface calculations be for predicting relative binding affinities? Acetylcholinesterase huprine inhibitors as a test case

Abstract

This study examines the accuracy of molecular dynamics-linear response (MD/LR) and Poisson± Boltzmann/solvent accessible surface (PB/SAS) calculations to predict relative binding anities. A series of acetylcholinesterase (AChE) huprine inhibitors has been chosen as a test system owing to the availability of freeenergy (thermodynamic integration) calculations. The results obtained with the MD/LR approach point out a clear relationship between the experimental anity and the electrostatic interaction energy alone for a subset of huprines, but the suitability of the MD/LR approach to predict the binding anity of the whole series of compounds is limited. On the other hand, PB/SAS calculations show a marked dependence on both the computational protocol and the nature of the inhibitor± enzyme complex.

Pyrano[3,2-c]quinoline−6-Chlorotacrine Hybrids as a Novel Family of Acetylcholinesterase- and β-Amyloid-Directed Anti-Alzheimer Compounds

“…In all cases the most favorable binding is found for target C, as this binding mode is favored by 4.3-7.6 and 2.4-9.9 kcal/mol when dielectric permittivities of 2 and 4 are considered for the interior of the ligand-hAChE complex, respectively, relative to the second most stable complex. Moreover, the results also show that there are small differences in the affinities estimated for the binding of hybrids 20, 25, and 27 to target C. Keeping in mind the range of uncertainty expected for MM-PBSA calculations, 80,82 this finding is in agreement with the similar inhibitory potencies measured for these compounds (IC 50 values ranging from 7 to 14 nM, Table 1). …”

Acetylcholinesterase: Molecular Modeling with the Whole Toolkit

“…Conversely, when modeling huprine-X it was found that the amalgamation of chemical features from the noncovalent esteratic active site inhibitor huperzine and the gorge binding tacrine led to an extremely strongly binding noncovalent inhibitor spanning both the nucleophilic active site and the lipophilic gorge [50,51]. It was also noted that huprine-X was found to bind significantly more strongly to tcAChE than to huAChE, thus highlighting the importance of the Phe to Tyr mutation (tcAChE: Phe 330 / huAChE: Tyr337) distinguishing the two structures [50,51]. Both the tacrine analog and the huprine-X studies demonstrated the analytical power of MD methods for effective pharmacophore mapping within a complex, multifunctional receptor such as that of AChE.…”

“…In the tacrine studies, simulations on increasingly hydrophobic analogs suggest that such hydrophobicity produces important changes in the binding mode away from the gorge binding location of tacrine itself, exhibiting simultaneous lipophilic stacking with Trp84 and Phe330 (according to tcAChE numbering; huAChE = Trp86, Tyr337) and yielding an inhibitive mechanism arising more from PAS-binding interactions, thus raising the prospect of tailoring inhibitors toward simultaneous complexation with both subsites [48,49]. Conversely, when modeling huprine-X it was found that the amalgamation of chemical features from the noncovalent esteratic active site inhibitor huperzine and the gorge binding tacrine led to an extremely strongly binding noncovalent inhibitor spanning both the nucleophilic active site and the lipophilic gorge [50,51]. It was also noted that huprine-X was found to bind significantly more strongly to tcAChE than to huAChE, thus highlighting the importance of the Phe to Tyr mutation (tcAChE: Phe 330 / huAChE: Tyr337) distinguishing the two structures [50,51].…”

“…In addition to the aforementioned study of PAS-binding fasciculin-AChE complexes [34] and more recent work on this system by the same group [45], there has been research on the dynamics of the non-covalent active-site binding huperzine [30], precomplexation studies on ACh and various of its analogs [46], and examinations of PAS-binding inhibitors such as the Alzheimers drug propidium [47], tacrine analogs [48,49], and of the novel tacrine-huperzine hydrid huprine-X [50,51]. As discussed in previous paragraphs in this section, the research on fasciculin binding was primarily geared toward elucidation of connections between ligand binding and the formation of the back and side door conduits [46].…”

Estimation of the Binding Free Energy by Linear Interaction Energy Models

“…Among others, this survey will be focused on the Extended Linear Response (ELR) [15][16][17]; the surface generalized Born LIE (SGB-LIE) [18]; the molecular mechanics generalized Born surface area (MM-GB/SA) and its Poisson-Boltzman variant (MM-PB/SA) [19][20][21][22][23], the linear interaction energy in continuum electrostatics (LIECE) and its quantum mechanics variant (QMLIECE) [24].…”