FLUFF-BALL, A Template-Based Grid-Independent Superposition and QSAR Technique:  Validation Using a Benchmark Steroid Data Set

Abstract

The Flexible Ligand Unified Force Field (FLUFF) is a molecular mechanistic superposition algorithm utilizing a template structure, on top of which the ligand(s) are superimposed. FLUFF enables a flexible semiautomatic superimposition in which the ligand and the template are allowed to seek the best common conformation, which can then be used to predict the biological activity by Boundless Adaptive Localized Ligand (BALL). In BALL, the similarity of the electrostatic and van der Waals volumes of the template and ligand is evaluated using the template-based coordinate system which makes the FLUFF-BALL invariant as to the rotations and translations of the global coordinate system. When tested using the CBG (corticosteroid binding globulin) affinities of 31 benchmark steroids, the FLUFF-BALL technique produced results comparable to standard 3D-QSAR methods. Supplementary test calculations were performed with five additional data sets. Due to its high level of automation and high throughput, the FLUFF-BALL is highly suitable for use in drug design and in scanning of large molecular libraries.

SOMFA on Large Diverse Xenoestrogen Dataset: The Effect of Superposition Algorithms and External Regression Tools

“…FLUFF [46] is a superimposition force field based on a modified Merck Molecular Force Field (MMFF94) [51 -55], which enables the use of several well-documented and tested computational techniques of molecular mechanics. The actual superimposition is accomplished by performing a geometry optimization by using the superimposition force field.…”

“…Instead, a term is added describing the van der Waals and electrostatic similarity of the ligand and the template using Gaussian type functions (e x n ) which are also used in the SEAL [19] superposition algorithm. For full technical details of the FLUFF algorithm the reader is referred to the original article [46]. The current implementation of the FLUFF superposition algorithm provides three main variants, FIX, MIX, and FLEX, all of them being utilized in this work.…”

“…As FLUFF is in essence a special molecular mechanics force field, the atom types could be used to provide additional information. However, trial runs performed using other datasets [46] have indicated that this kind of selectivity works well only in cases where the molecules are fairly similar. Unfortunately, this is not the case with the EDKB data, and other constraints for guiding the superposition must be used.…”

“…In this paper SOR, MCSOR, and SIMPLS are used to evaluate the performance of SOMFA on a large and diverse xenoestrogen dataset. Furthermore, the effect of polarizibility descriptor [45] along with Flexible Ligand Unified Forcefield (FLUFF) [46] and SEAL [19] superposition techniques on the predictive ability of SOMFA is evaluated.…”

Influence of conformation on the representation of small flexible molecules at low resolution: alignment of endothiapepsin ligands

“…Molecular flexibility can also be treated by considering, as above, only one initial conformation, but allowing its geometrical parameters to be modified during the alignment or docking process [34][35][36][37][38][39]. In those cases, molecular geometry is often directly implied in the calculation of a scoring index through molecular mechanics type formulae [22,37,38], or feature-based formulae [36] such as volume, aromaticity, H-bond donor/ acceptor, molecular refractivity, surface exposure, .…”