Method for Searching Compound Databases Using Topomeric Shape Descriptors and Pharmacophoric Features Identified by a Comparative Molecular Field Analysis (CoMFA) Utilizing Topomeric Alignment of Molecular Fragments

• US 20090228463A1
• Filed: 03/10/2008
• Published: 09/10/2009
• Est. Priority Date: 03/10/2008
• Status: Abandoned Application

• Current Assignee: Brian Campbell, Richard D. Cramer
• Original Assignee: Brian Campbell, Richard D. Cramer
• Inventors: Campbell, Brian, Cramer, Richard D.
• Application Number:
  US12/045,511
• Publication Number:
  US 20090228463A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: G16C 20/30 Prediction of properties of chemical compounds, compositions or mixtures
• CPC Class Codes: G16C 20/40 Searching chemical structures or physicochemical data

Abstract

A CoMFA 3D QSAR shape analysis may be performed on molecules arising from the same activity series that may be decomposed/viewed as assemblies of discrete identifiable subunits. The disclosed method provides for identifying in databases of whole molecules those molecular subunits that possess the same shape or shape and feature characteristics as the subunits of molecules used to perform the CoMFA analysis. Additionally, the method provides for estimation of the likely biological activity of molecules assembled from the subunits identified in the molecular database.

Claims

1. A computer implemented method for identifying fragments from a heterogeneous compound database which are likely to share the same type of activity as fragments derived from molecules identified as sharing that activity, comprising the steps of:

(a) fragmenting the molecules in the series according to a consistent procedure;

(b) topomerically aligning each fragment according to a defined set of rules;

(c) calculating steric and electrostatic field descriptor values for the topomerically aligned fragments;

(d) entering the field descriptor values in a CoMFA table wherein the field descriptors for each fragment are associated with the unique parameter value for the molecule from which the fragment was derived;

(e) analyzing the table with the CoMFA methodology to derive a 3D CoMFA QSAR model generating coefficients of each field descriptor value in the 3D CoMFA QSAR table;

(f) using the steric field values of the fragments in the CoMFA table, searching a heterogeneous compound database for fragments, the database compounds similarly fragmented and the fragments topomerically aligned and characterised by steric and electrosatic field descriptors, to identify those fragments having shapes similar to the fragments used to generate the 3D CoMFA QSAR; and

(g) determining the likely activity of fragments identified as being similar in shape by determining the likely activity for each fragment by multiplying the steric and electrostatic field values for each fragment by the 3D CoMFA QSAR coefficients of the similarly positioned fragments derived from molecules in the initial activity series.

2. A computer implemented method for identifying fragments from a heterogeneous compound database which are likely to share the same type of activity as fragments derived from molecules identified as sharing that activity, comprising the steps of:

(a) fragmenting the molecules in the series according to a consistent procedure;

(b) topomerically aligning each fragment according to a defined set of rules;

(c) calculating steric and electrostatic field descriptor values for the topomerically aligned fragments;

(d) characterising the type and location of features in the topomerically aligned fragments;

(e) entering the field descriptor values in a CoMFA table wherein the field descriptors for each fragment are associated with the unique parameter value for the molecule from which the fragment was derived;

(f) analyzing the table with the CoMFA methodology to derive a 3D CoMFA QSAR model generating coefficients of each field descriptor value in the 3D CoMFA QSAR table;

(g) using the steric field values of the fragments in the CoMFA table and features, searching a heterogeneous compound database for fragments, the database compounds similarly fragmented and the fragments topomerically aligned and characterised by steric and electrosatic field descriptors and features, to identify those fragments having shapes similar ande features to the fragments used to generate the 3D CoMFA QSAR; and

(h) determining the likely activity of fragments identified as being similar in shape by determining the likely activity for each fragment by multiplying the steric and electrostatic field values for each fragment by the 3D CoMFA QSAR coefficients of the similarly positioned fragments derived from molecules in the initial activity series.

3. A computer implemented method for predicting the likely activity of molecules which are likely to share the same type of activity as molecules of an activity series, comprising the steps of:

(a) fragmenting the molecules in the series according to a consistent procedure;

(b) topomerically aligning each fragment according to a defined set of rules;

(c) calculating steric and electrostatic field descriptor values for the topomerically aligned fragments;

(d) characterising the type and location of features in the topomerically aligned fragments;

(e) entering the field descriptor values in a CoMFA table wherein the field descriptors for each fragment are associated with the unique parameter value for the molecule from which the fragment was derived;

(f) analyzing the table with the CoMFA methodology to derive a 3D CoMFA QSAR model generating coefficients of each field descriptor value in the 3D CoMFA QSAR table;

(g) using the steric field values and features of the aligned fragments, searching a heterogeneous compound database for fragments, the database compounds similarly fragmented and the fragments topomerically aligned, characterised by steric and electrosatic field descriptors and features, to identify those fragments having shapes and features similar to the fragments used to generate the 3D CoMFA QSAR; and

(h) determining the likely activity of molecules formed, when fragments from the heterogeneous compound database, identified as being similar in shape and features, are used to replace the fragments from the molecules in the initial activity series, by multiplying the steric and electrostatic field values for each database derived fragment by the 3D CoMFA QSAR coefficients of the similarly positioned fragment derived from molecules in the initial activity series.