Comparative field analysis (CoMFA) utilizing topomeric alignment of molecular fragments
View Patent ↗The static and electrostatic interaction energy fields between probe atoms and the atoms of a topomerically aligned fragment placed in a three-dimensional grid may be used to derive a CoMFA model. The topomeric CoMFA model coefficients may be used to predict partial activity values for fragments not derived from molecules of the activity series. The partial activities can be summed to provide a predicted activity for all fragment positions of the activity series molecules. A Virtual Library in which topomerically aligned fragments are associated with their respective steric and electrostatic interaction energies can be searched for fragments similar in shape to the fragments derived from the molecules of the activity series. The identified fragments can be used with the topomeric CoMFA coefficients to predict their activity if used in the molecular activity series.
1. A computer implemented method of generating a three-dimensional quantitative structure activity relationship (3D QSAR) of a series of molecules previously identified as having related chemical or biological properties described by a unique parameter value for each molecule in the 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) 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; and
(e) analyzing the table with the CoMFA methodology
wherein the correlation among the molecules in the series is visually displayed.
2. A computer implemented method for predicting the likely activity of a molecule of interest based upon the activities and three dimensional shapes of a series of molecules previously identified as having related chemical or biological properties described by a unique parameter value for each molecule in the 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) 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 generating coefficients of each field descriptor value in the 3D CoMFA QSAR table;
(f) fragmenting the molecule of interest according to the same consistent procedure as used to fragment the molecules in the series;
(g) topomerically aligning each fragment according to the same defined set of rules as used to align the fragments derived from the molecules in the series;
(h) calculating steric and electrostatic field descriptor values for the topomerically aligned fragments;
(i) entering the field descriptor values for the fragments derived from the molecule of interest in the 3D CoMFA QSAR table; and
(j) generating a predicted activity by multiplying the field descriptor values for the fragments derived from the molecule of interest by the associated previously derived 3D CoMFA QSAR coefficients and summing the results
wherein the activity predicted for the molecule of interest is made available to a user.
3. A computer implemented method of identifying additional molecules which are likely to share the same type of activity as molecules previously identified as sharing the same type of 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 generating coefficients of each field descriptor value in the 3D CoMFA QSAR table;
(f) using the steric field values of the aligned fragments, searching molecular fragments not derived from the molecules previously identified as sharing the same type of activity, the additional molecular fragments similarly 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;
(g) determining the likely activity of molecules formed when fragments identified as being similar in shape are used to replace the fragments generated from the molecules previously identified as sharing the same type of activity by the following steps:
(1) determining partial activities for each fragment by multiplying the field values for each fragment by the 3D CoMFA QSAR coefficients of the similarly positioned fragment derived from the initial molecules;
(2) ranking the fragments for each fragment position by partial activity values; and
(3) combinatorially summing all possible combinations of partial activity values of the fragments, observing fragment position order, to obtain predicted activities for molecules assembled from the identified fragments
wherein the structures of molecules assembled from ranked fragments are identified to a user along with their associated predicted activities.
4. A computer implemented method of identifying additional molecules which are likely to share the same type of activity as molecules previously identified as sharing the same type of 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 generating coefficients of each field descriptor value in the 3D CoMFA QSAR table;
(g) using the steric field values of the aligned fragments, searching molecular fragments not derived from the molecules previously identified as sharing the same type of activity, the additional molecular fragments similarly topomerically aligned and characterised by steric and electrostatic field descriptors and features, to identify those fragments having both shapes and feature types and location similar to the fragments used to generate the 3D CoMFA QSAR;
(h) determining the likely activity of molecules formed when fragments identified as being similar in shape and features are used to replace the fragments generated from the molecules previously identified as sharing the same type of activity by the following steps:
(1) determining partial activities for each fragment by multiplying the field values for each fragment by the 3D CoMFA QSAR coefficients of the similarly positioned fragment derived from the initial molecules;
(2) ranking the fragments for each fragment position by partial activity values; and
(3) combinatorially summing all possible combinations of partial activity values of the fragments, observing fragment position order, to obtain predicted activities for molecules assembled from the identified fragments
wherein the structures of molecules assembled from ranked fragments are identified to a user along with their associated predicted activities.