J Chem Inf Model - Exploration of 3D activity cliffs on the basis of compound binding modes and comparison of 2D and 3D cliffs.


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Activity cliffs are formed by pairs or groups of structurally similar compounds having large differences in potency and are focal points of structure-activity relationship (SAR) analysis. The choice of molecular representations is a critically important aspect of activity cliffs analysis. Thus far, activity cliffs have predominantly been defined on the basis of molecular graph or fingerprint representations. Herein we introduce 3D activity cliffs derived from comparisons of experimentally determined compound binding modes. The analysis of 3D activity cliffs is generally applicable to target proteins for which structures of multiple ligand complexes are available. For two popular targets, ?-secretase 1 (BACE1) and factor Xa (FXa), public domain X-ray structures with bound inhibitors were collected. Crystallographic binding modes of inhibitors were systematically compared using a 3D similarity method taking conformational, positional, and atomic property differences into account. In addition, standard 2D similarity relationships were also determined. SAR information associated with individual compounds substantially changed when either bioactive conformations or 2D molecular graphs were used for similarity evaluation. 3D activity cliffs were identified for BACE1 and FXa inhibitor sets and systematically compared to 2D cliffs. It was found that less than 40% of 3D activity cliffs were conserved when 2D similarity was applied. The limited conservation of 3D and 2D cliffs provides further evidence for the strong molecule representation dependence of activity cliffs. Moreover, 3D cliffs represent a new class of activity cliffs that convey SAR information in ways that differ from graph-based similarity measures. In cases where sufficient structural information is available, the comparison of 3D and 2D cliffs is expected to aid in SAR analysis and mapping of critical binding determinants.

Resumo Limpo

activ cliff form pair group structur similar compound larg differ potenc focal point structureact relationship sar analysi choic molecular represent critic import aspect activ cliff analysi thus far activ cliff predomin defin basi molecular graph fingerprint represent herein introduc d activ cliff deriv comparison experiment determin compound bind mode analysi d activ cliff general applic target protein structur multipl ligand complex avail two popular target secretas bace factor xa fxa public domain xray structur bound inhibitor collect crystallograph bind mode inhibitor systemat compar use d similar method take conform posit atom properti differ account addit standard d similar relationship also determin sar inform associ individu compound substanti chang either bioactiv conform d molecular graph use similar evalu d activ cliff identifi bace fxa inhibitor set systemat compar d cliff found less d activ cliff conserv d similar appli limit conserv d d cliff provid evid strong molecul represent depend activ cliff moreov d cliff repres new class activ cliff convey sar inform way differ graphbas similar measur case suffici structur inform avail comparison d d cliff expect aid sar analysi map critic bind determin

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