Common protein surface shapes and uses therefor

Abstract

A method of determining common three-dimensional structural features of protein surfaces is provided, as is use of representations of these common structures in molecular database searching and in designing focussed molecular libraries. The method is particularly concerned with the analysis and representation of protein surfaces such as b-turns, loops and contact surfaces. In one form, the method identifies common locations and orientations of amino acid side-chains, simplified as Cα-Cβ vectors. In another form, the method identifies common regions of surface charge represented by grid points in three-dimensional space. Further provided are common three dimensional structural features of proteins that can be used to search molecular databases for the purposes of identifying molecules that match these common three dimensional structural features. The common three dimensional structural features can also be used to focus de novo molecular generation to produce libraries containing molecules that have these common three dimensional structural features. Libraries of these structurally-related molecules may then be produced for the purposes of drug discovery.

Description

FIELD OF THE INVENTION [0001] THIS INVENTION relates to a method of determining common three-dimensional structural features of proteins and use of representations of these common structures in molecular database searching, in molecular engineering and in designing focussed molecular libraries. More particularly, this invention relates to the identification and representation of protein surfaces such as α-turns, loops and contact surfaces and the determination of grid points describing surface charge, or the determination of common locations and orientations of amino acid side-chains, simplified as Cα-Cβ vectors. These protein surfaces are typically involved in interactions with other molecules such as other proteins, nucleic acids, metal ions, antigens, drugs and toxins although without limitation thereto. This invention therefore provides common three-dimensional structural features that can be used to search molecular databases for the purposes of identifying molecules that match...

AI Technical Summary

Benefits of technology

The present invention provides a method for identifying common protein surface shapes and using them to design, engineer, and screen molecules. The method involves creating descriptors that represent the common surface shapes of multiple proteins, which can then be used to search a database and identify molecules that match the descriptors. The molecules can then be used to create a library of molecules or engineered to include the common surface shapes. The technical effect of this invention is the ability to efficiently design and screen molecules that interact with protein surfaces, which can be useful in drug discovery and material science.

Problems solved by technology

With hundreds of potential descriptors it is difficult to know which descriptors are important or essential for describing biological activity.

These approaches consequently optimise libraries in the chemical universe but do not identify molecules that could modulate biological function.

Whilst the description of protein structure by the nature of its polymeric backbone (its “skeleton”) is useful for comparing one protein to another, it is not useful when describing the structural elements of various molecular recognition events of proteins.

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