Flexible Alignment of Small Molecules Using the Penalty Method

Abstract

An efficient flexible alignment method using the penalty method, called FAP, is described. FAP is a pairwise alignment algorithm that matches a flexible sample to a rigid template. It is a pure atom-based 3D method that utilizes the modified SEAL similarity index combined with an energy penalty term. The penalty term, defined as the third power of the ratio of the local strain energy to its target value, enables effective control of energy increase during alignment. The alignment procedure consists of the seed conformer generation, rigid-body alignment, and flexible optimization steps. Both conformation and alignment spaces are efficiently explored by the sparse, random sampling schemes. FAP has been tested with benchmark sets of seven different classes of ligands taken from the literature. In terms of the ability to produce the bioactive overlays, FAP is comparable to, or in some cases better than, other alignment methods. FAP is accurate, objective, fully automated, and fast enough to be used as a tool for virtual screening.

Training a Scoring Function for the Alignment of Small Molecules

“…4,16,19,20 In light of this, we tried out a total of 7 values for α a , from 0.06 to 0.7 Å −2 . The corresponding numbers of good poses among the top 25 are tabulated in Table 2a.…”

“…While the Gaussian function is widely used in molecular alignment methods (e.g., FAP, Pharao, MOE, SQ, and SEAL), there are other functional forms that can provide a similar effect. These include piecewise linear functions (e.g., FLAME), and piecewise linear and quadratic functions (e.g., TFIT) .…”

“…In light of the importance of the subject, many methods have been developed to perform the task. On top of the methods mentioned in the comprehensive review of Lemmen and Lengauer, new efforts have continued to appear. − …”

“…On top of the methods mentioned in the comprehensive review of Lemmen and Lengauer, 2 new efforts have continued to appear. [3][4][5][6][7][8][9][10][11][12][13][14][15][16] Similar to docking, the small molecule alignment problem can be divided into two parts. First, the conformational/pose space has to be thoroughly searched.…”

pharmACOphore: Multiple Flexible Ligand Alignment Based on Ant Colony Optimization

“…ROCS [12][13][14] (Rapid OVerlay of Chemical Structures) from OpenEye is a shape matching application maximizing the overlap of smooth Gaussian functions representing the molecular volumes of the ligand structures. Shin et al 15 used a modified SEAL similarity index 16 combined with an energy penalty term to generate pairwise alignments. LigMatch 17 is based on a geometric hashing method.…”