Normal-Mode-Analysis–Monitored Energy Minimization Procedure for Generating Small–Molecule Bound Conformations

Abstract

The energy minimization of a small molecule alone does not automatically stop at a local minimum of the potential energy surface of the molecule if the minimum is shallow, thus leading to folding of the molecule and consequently hampering the generation of the bound conformation of a guest in the absence of its host. This questions the practicality of virtual screening methods that use conformations at local minima of their potential energy surfaces (local minimum conformations) as potential bound conformations. Here we report a normal-mode-analysis–monitored energy minimization (NEM) procedure that generates local minimum conformations as potential bound conformations. Of 22 selected guest–host complex crystal structures with guest structures possessing up to four rotatable bonds, all complexes were reproduced, with guest mass–weighted root mean square deviations of <1.0 Å, through docking with the NEM–generated guest local minimum conformations. An analysis of the potential energies of these local minimum conformations showed that 22 (100%), 18 (82%), 16 (73%), and 12 (55%) of the 22 guest bound conformations in the crystal structures had conformational strain energies of less than or equal to 3.8, 2.0, 0.6, and 0.0 kcal/mol, respectively. These results suggest that (1) the NEM procedure can generate small–molecule bound conformations, and (2) guests adopt low-strain–energy conformations for complexation, thus supporting the virtual screening methods that use local minimum conformations.

Structure of HI-6•Sarin-Acetylcholinesterase Determined by X-Ray Crystallography and Molecular Dynamics Simulation: Reactivator Mechanism and Design

“…It is worth noting that no energy minimization was performed on A2C. This large RMSD difference is, however, caused partly by crystal packing [36] , [37] and partly by the uncertainties of residues with high B factors. To minimize the difference caused by crystal packing and high B factors, we propose to use the RMSD of alpha-carbon atoms for residues that are not involved in crystal contact and have B factors of alpha-carbon atoms lower than the average alpha-carbon B factor.…”

Common Pharmacophore of Structurally Distinct Small-Molecule Inhibitors of Intracellular Retrograde Trafficking of Ribosome Inactivating Proteins

“…These conformations also superimpose well with the local minimum conformations of ( S )-Retro-1 6 and Compound 75 25 , both of which are effective intracellular RIP transport inhibitors ( Figure 3 ). It is now well accepted that small molecules do not necessarily adopt their lowest potential energy conformations but do adopt local minimum conformations when binding to proteins 26 27 . All the chemical structures shown in Figure 3 are rigid.…”

EUDOC on the IBM Blue Gene/L system: Accelerating the transfer of drug discoveries from laboratory to patient

“…However, the conformation induction approach is not ideal for docking studies because computing the mutually dependent conformational changes of both ligand and receptor is time consuming. Alternatively, the conformation selection theory involves a scenario in which both ligand and receptor select their preformed conformations that are most compatible with each other to effect binding by shifting two equilibriums progressively from less-compatible to most-compatible conformations for both partners [19][20][21][22][23][24], where the preformed conformations are conformations at the local minima of their potential energy surfaces (i.e., local minimum conformations). When the most compatible conformers of ligand and receptor are the most prevalent, the conformation selection theory becomes the lock-key theory [18].…”