Dihedral Angle-Based Sampling of Natural Product Polyketide Conformations: Application to Permeability Prediction

Abstract

Macrocycles pose challenges for computer-aided drug design due to their conformational complexity. One fundamental challenge is identifying all low-energy conformations of the macrocyclic ring, which is important for modeling target binding, passive membrane permeation, and other conformation-dependent properties. Macrocyclic polyketides are medically and biologically important natural products characterized by structural and functional diversity. Advances in synthetic biology and semisynthetic methods may enable creation of an even more diverse set of non-natural product polyketides for drug discovery and other applications. However, the conformational sampling of these flexible compounds remains demanding. We developed and optimized a dihedral angle-based macrocycle conformational sampling method for macrocycles of arbitrary structure, and here we apply it to diverse polyketide natural products. First, we evaluated its performance using a data set of 37 polyketides with available crystal structures, with 9-22 rotatable bonds in the macrocyclic ring. Our optimized protocol was able to reproduce the crystal structure of polyketides' aglycone backbone within 0.50 Å RMSD for 31 out of 37 polyketides. Consistent with prior structural studies, our analysis suggests that polyketides tend to have multiple distinct low-energy structures, including the bioactive (target-bound) conformation as well as others of unknown significance. For this reason, we also introduce a strategy to improve both efficiency and accuracy of the conformational search by utilizing torsional restraints derived from NMR vicinal proton couplings to restrict the conformational search. Finally, as a first application of the method, we made blinded predictions of the passive membrane permeability of a diverse set of polyketides, based on their predicted structures in low- and high-dielectric media.

Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs

“…The results were validated within 10 % using standard methods, that is, by the addition of random noise (max 10 %) to the experimental data, by the random removal of individual restraints (10 %), and by comparison of the experimentally observed and back‐calculated distances. Macrocycle core conformations were classified as different if their heavy atom root‐mean‐square deviation (RMSD) was >0.5 Å, while a >0.75 Å heavy atom cut off was used for the overall macrocycle including side chains. All conformations for each macrocycle in the two solvents, with the corresponding molar fractions, are given in the Supporting Information, Section 6.…”

Computational Methodologies in the Exploration of Marine Natural Product Leads

“…Low-energy conformations must be identified to model conformation-dependent properties. Macrocyclic polyketides are medically and biologically important NPs characterized by structural and functional diversity [ 145 ]. Wang et al proposed an improved dihedral angle-based macrocycle conformational sampling method and evaluated its performance with a data set of 37 polyketides with 9−22 rotatable bonds in the macrocyclic ring for which crystal structures were available [ 145 ].…”

“…Macrocyclic polyketides are medically and biologically important NPs characterized by structural and functional diversity [ 145 ]. Wang et al proposed an improved dihedral angle-based macrocycle conformational sampling method and evaluated its performance with a data set of 37 polyketides with 9−22 rotatable bonds in the macrocyclic ring for which crystal structures were available [ 145 ]. The protocol was able to reproduce the crystal structure of polyketides’ aglycone backbone within an RMSD of 0.50 Å for 31 out of 37 polyketides [ 145 ].…”

Prediction of Passive Membrane Permeability by Semi‐Empirical Method Considering Viscous and Inertial Resistances and Different Rates of Conformational Change and Diffusion

“…The major approaches are random search and systematic search. [40][41][42][43][44][45][46][47] Especially, the conformer generation of ring systems is more difficult than that of nonring systems. For ring systems, some specialized methods, such as corner and edge flips, have been used.…”