ConfGen: A Conformational Search Method for Efficient Generation of Bioactive Conformers

Abstract

We describe the methodology, parametrization, and application of a conformational search method, called ConfGen, designed to efficiently generate bioactive conformers. We define efficiency as the ability to generate a bioactive conformation within a small total number of conformations using a reasonable amount of computer time. The method combines physics-based force field calculations with empirically derived heuristics designed to achieve efficient searching and prioritization of the ligand's conformational space. While many parameter settings are supported, four modes spanning a range of speed and quality trades-offs are defined and characterized. The validation set used to test the method is composed of ligands from 667 crystal structures covering a broad array of target and ligand classes. With the fastest mode, ConfGen uses an average of 0.5 s per ligand and generates only 14.3 conformers per ligand, at least one of which lies within 2.0 A root-mean-squared deviation of the crystal structure for 96% of the ligands. The most computationally intensive mode raises this recovery rate to 99%, while taking 8 s per ligand. Combining multiple search modes to "fill-in" holes in the conformation space or energy minimizing using an all-atom force field each lead to improvements in the recovery rates at higher resolutions. Overall, ConfGen is at least as good as competing programs at high resolution and demonstrates higher efficiency at resolutions sufficient for many downstream applications, such as pharmacophore modeling.

<strong>LIGAND-BASED PHARMACOPHORE MODEL AND QSAR STUDIES ON HERBICIDES TARGETING PHOTOSYSTEM II FROM CHLAMYDOMONAS REINHARDTII</strong>

“…All structures were converted from smiles code into 3D structures, and ionization states and tautomers in the pH range of 6.2±0.3 were generated, using the LigPrep module [8] of Schrödinger suite [9]. The conformational space for each ligand was developed with the help of ConfGen module [10,11] using the default options. 217 compounds resulted after conformer generation and energy minimization based on the OPLS-2005 force field.…”

Discovery of Some Potent PDHK Inhibitors Using Pharmacophore Modeling, Virtual Screening and Molecular Docking Studies

“…The conformers for each molecule were generated by running a mixed MCMM/LMOD (Mixed Monte Carlo Multiple Minimum/ Low Mode) search [21] with a distance-dependent dielectric solvation treatment and the OPLS-2005 force-field. For each molecule, the conformers with a maximum energy difference of 10 kcal mol-1 relative to the global energy minimum conformer were retained.…”

3D-QSAR Study of Melanin Inhibiting (S)-(+)-Decursin and its Analogues by Pharmacophore Mapping

“…18 Conformers were generated during search using ConfGen module. 15 We imposed the condition that all molecules must match on at least 7 site points with distance matching tolerance 1.0 Å, with other parameters in default setting.…”