BCL::MolAlign: Three-Dimensional Small Molecule Alignment for Pharmacophore Mapping

Abstract

Small molecule flexible alignment is a critical component of both ligand-and structure-based methods in computer-aided drug discovery. Despite its importance, the availability of high-quality flexible alignment software packages is limited. Here, we present BCL::MolAlign, a freely available property-based molecular alignment program. BCL::MolAlign accommodates ligand flexibility through a combination of pregenerated conformers and on-the-fly bond rotation. BCL::MolAlign converges on alignment poses by sampling the relative orientations of mutually matching atom pairs between molecules through Monte Carlo Metropolis sampling. Across six diverse ligand data sets, BCL::MolAlign flexible alignment outperforms MOE, ROCS, and FLEXS in recovering native ligand binding poses. Moreover, the BCL::MolAlign alignment score is more predictive of ligand activity than maximum common substructure similarity across 10 data sets. Finally, on a recently published benchmark set of 20 high quality congeneric ligand-protein complexes, BCL::MolAlign is able to recover a larger fraction of native binding poses than maximum common substructure-based alignment and ROSETTALIGAND. BCL::MolAlign can be obtained as part of the BIOLOGY AND CHEMISTRY LIBRARY (BCL) software package freely with an academic license or can be accessed via Web server at http://meilerlab.org/ index.php/servers/molalign.

General Purpose Structure-Based Drug Discovery Neural Network Score Functions with Human-Interpretable Pharmacophore Maps

“…These atomic features are a superset of those we used previously for QSAR, 5 , 14 and are identical to those we used previously for the superimposition of similar molecules. 44 …”

In-silico screening for identification of potential inhibitors against SARS-CoV-2 transmembrane serine protease 2 (TMPRSS2)

“…The hit compounds were used for Clustering through Soergel (Tanimoto Coefficient) Distance method and Ward linkage Clustering method with clustering Threshold was 0.9. After this, we check the structural difference between known Camostat and other hit compounds using MolAlign Server based on property-based small molecule alignment; for this alignment, we used full-flexible alignment ( Brown et al, 2019 ).…”

Lipocalin Blc is a potential heme‐binding protein

“…Starting coordinates for hematoporphyrin (HP) are based on the common atom coordinates in the crystallographically determined pose of heme in complex with wtBlc‐split fit with a maximum common substructure alignment [26]. Split site residues were remodeled with Rosetta comparative modeling (RosettaCM) using a previously solved crystallographic structure of wtBlc (PDB ID https://doi.org/10.2210/pdb1QWD/pdb) to obtain a model of the intact wtBlc.…”