“Quasi flexible” automatic docking processing for studying stereoselective recognition mechanisms, part 2: Prediction of ΔΔG of complexation and ¹H‐NMR NOE correlation

Abstract

The purpose of this work is to apply the global molecular interaction evaluation ("Glob-MolInE") computational protocol to the study of two molecular complexes characterized by a chiral selector and a couple of enantiomeric selectands experimentally known to give large difference in the free energy of complexation much higher than the experimental error normally associated to the molecular mechanic calculations. We have considered the well known diastereomeric complexes between the selector (S)-N-(3,5-dinitrobenzoyl)-leucine-n-propylamide (S)-1 and the selectands (R) or (S)-N-(2-naphthyl)-alanine methyl ester 2, widely studied by enantioselective HPLC, NMR and X-ray. The experimental difference of free energy of complexation between [(S)-1*(R)-2] and [(S)-1*(S)-2] (-1.34 kcal/mol) was reproduced by the new computational protocol with an excellent confidence error. Detailed results about the conformational search, the "quasi-flexible" docking and the thermodynamic estimation are presented in this work. A remarkable correlation between the theoretical results and experimental data (NOE measurements, X-ray crystallographic structure of the [(S)-1*(S)-2] complex and the free energy of complexation) supports the validity of the computational approach and underline the importance of the conformational multiplicity in the definition of the macroscopic properties of the complex in solution.

NMR and Computational Investigations of the Chiral Discrimination Processes Involving a Cyclic Tetraamidic Chiral Selector

“…[10][11][12] Structures of host and guest were obtained by conformational search carried out by the Batchmin program of Macromodel version 4.5 (Columbia University, NY) using the following options: MM2 Force Field, using the GB/SA solvation model for chloroform, Montecarlo stochastic algorithm with 3000 generated structures, minimization by PR conjugate gradient. All rotatable bonds were explored.…”

“…As for any other NMR parameter of the fast-exchanging monomer/dimer system, these two values of τ c obs represent the weighted averages of the values corresponding to the pure monomer (τ c m ) and dimer (τ c d ) species, which can be calculated from Equation (11) for the two observed values. (11) In this way, for the monomer and dimer, we obtained correlation times of 10.5 and 33.2 ps, which reflect the significant slowing down of the molecular motion as a result of the self-association of monomer units of 2.…”

“…[10][11][12] The large number of conformations predicted for 2 (77 different structures within 3 kcal/mol of the global minimum, accounting for a Boltzmann population of 98 %) prompted us to generate a smaller number of structures of 2 that are representative of the whole 2-conf ensemble (see Experimental Section) to be used in the docking procedure. The docking simulation, using 52 different approaching directions and 272 different relative orientations of the two molecules, gave a final ensemble of 10 docked structures, 2-Dim, all lying within a 3 kcal/mol energy window.…”

Synthesis and biological evaluation of N-substituted-3,5-diphenyl-2-pyrazoline derivatives as cyclooxygenase (COX-2) inhibitors

“…the cleft occupied by SC-588 into the PDB original model (Supplementary Data). In order to evaluate the binding modes of all docked compounds we have considered both the default AutoDockeVina scoring function and the MolInE method [23,24] highlighting a good qualitative agreement with respect to the experimental inhibition IC 50 ( Table 2). The graphical analysis of the most stable COX-2 complexes revealed similar configuration for all docked pyrazoline derivatives.…”

The “Bridge” Game: Role of the Fourth Player in Chiral Recognition

“…(1) forms, an in depth theoretical study has been carried out by performing extensive "quasi-flexible" multiconformational molecular dockings based on molecular mechanics (MM) calculations (with the MM2 force field). [22,23] An extensive description of the adopted procedure is reported in the Supporting Information, together with its validation in assessing the factors responsible for the measured enantioselectivity of the selected A2B2-type tetra-amidic hosts towards chiral amino-acidic guests. By far the most accessible geometry assumed by the homo-and the heterochiral aggregates is characterized by the two all-eq/all-eq II R subunits in a tilted Yshaped disposition with the decamethylene bridges pointing outside.…”