Question

explain the details of COMFA
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Answer 1

Comparative Molecular Field Analysis: The desire to readily visualize QSARs in 3-D taking into account both whole molecule shapes as well as local structural features of a noncongeneric series of compounds using molecular graphic techniques provided the impetus for the development of comparative molecular field analysis (CoMFA) Cramer et al (1988). The idea is to create a type of 3-D contour map of the physicochemical forces surrounding a series of aligned compounds, and to treat each of the points in that 3-D contour map as structural descriptors to be correlated with biological activity. An assumption of the CoMFA is that the biological activity of molecules usually depends on complementary noncovalent molecular mechanics interactions with their receptor sites, which often can be adequately described by taking only steric (Van der Waals) and electrostatic (Coulombic) forces into account Cramer et al (1988). The CoMFA force field energies of a ligand interacting with its receptor are supposed to be mimicked by the point interactions of a probe atom with its ligand. In other words, the position-dependent steric and electrostatic contributions to the molecular force field energies surrounding the ligand serve as quantities that can be used as molecular descriptors for QSAR analysis and that can be visualized with computer graphics.

Answer 2

Answer:

COMFA {Comparative Molecular Field Analysis}

One of the critical points in CoMFA analysis is its limitation to a single conformation of each ligand. It is appropriately addressed in 4D QSAR (Hopfinger et al., 1997; Ekins et al., 1999; Vedani et al., 2000) in which each ligand molecule is presented by an ensemble of conformations, orientations, and protonation states, respectively.

The basic concept of 5D QSAR reflects the situation that accommodation of ligands into the binding site is often facilitated by the adaptation of the protein to the ligand topology (induced fit)—a mechanism triggered by the interaction between the small molecule and the protein. The induced fit may be local including rearrangement of few side chains or global by including main chain alterations (Vedani et al., 2006).

Steric Fields

In the first 3D-QSAR approach (the CoMFA method30), the steric field was computed by means of the Lennard-Jones (LJ) 6–12 potential energy between the ligand and a Csp3 probe. This field is characterized by a very sharp increase at short distances around the vdWS, thus requiring a cut-off value (usually +125 kJ mol−1), above which it must be truncated. The hardness of the LJ potential makes CoMFA results very sensitive to the relative orientation and precise alignment of molecules.  

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