Pharmacophores molecular electrostatic potentials

The final part is devoted to a survey of molecular properties of special interest to the medicinal chemist. The Theory of Atoms in Molecules by R. F.W. Bader et al., presented in Chapter 7, enables the quantitative use of chemical concepts, for example those of the functional group in organic chemistry or molecular similarity in medicinal chemistry, for prediction and understanding of chemical processes. This contribution also discusses possible applications of the theory to QSAR. Another important property that can be derived by use of QC calculations is the molecular electrostatic potential. J.S. Murray and P. Politzer describe the use of this property for description of noncovalent interactions between ligand and receptor, and the design of new compounds with specific features (Chapter 8). In Chapter 9, H.D. and M. Holtje describe the use of QC methods to parameterize force-field parameters, and applications to a pharmacophore search of enzyme inhibitors. The authors also show the use of QC methods for investigation of charge-transfer complexes. 

The descriptors developed to characterize the substrate chemotypes are obtained from a mixture of molecular orbital calculations and GRID probe-pharmacophore recognition. Molecular orbital calculations to compute the substrate s electron density distribution are the first to be performed. All atom charges are determined using the AMI Hamiltonian. Then the computed charges are used to derive a 3D pharmacophore based on the molecular electrostatic potential (MEP) around the substrate molecules. 

S. Guha, D. Majumdar, and A. K. Bhattacharjee, THEOCHEM, 88, 61 (1992). Molecular Electrostatic Potential A Tool for the Prediction of the Pharmacophoric Pattern of Drug Molecules. 

In the course of the pharmacophore identification process, clearly two different steps have to be taken in succession. First, a conformational analysis has to be carried out. After this initial step, a common three-dimensional arrangement of functional groups is determined through a superpositioning procedure. During the second step this preliminary sterical pharmacophore model has to be checked and consolidated by electron density calculations and establishment of the corresponding molecular electrostatic potentials (MEPs). 

Since the initial step in the formation of a dmg-receptor interaction complex is a recognition event, which is highly dependent on polar electrostatic interactions, one very easy and efficient way to test the so far purely steric pharmacophore model for significance is calculation of the molecular electrostatic potentials (MEPs) for all... 

Holtje, H.-D. (1992) Pharmacophore identification based on molecular electrostatic potentials. In Wermuth, C.G., Koga, N., Koenig, H. and Metcalf, B. (eds). Medicinal Chemistry for the 21st Century, pp. 181-189. Blackwell Scientific, Oxford. 

Kocjan, D., Hodoscek, M. and Hadzi, D. (1986) Dopaminergic pharmacophore of ergoline and its analogs. A molecular electrostatic potential study. J. Med Chem. 29 1418-1423. 

The concept of pharmacophore identification based on molecular electrostatic potentials has been reviewed [908]. Some other approaches to correlate biological activities with the interactions at certain positions of the binding site were discussed in chapter 2 (eqs. 17 and 18). 

The ligand overlap techniques we have considered so far use distances between ligand centers to determine potential pharmacophores. An alternative technique is to use overlap or difference measures of more continuous molecular properties, such as molecular electrostatic potential and molecular volume,... 

Figure 1 Different representations of a common RNA binding ligand neomycin B. (a) Molecular shape obtained by the calculation of the solvent accessible surface (MSA), (b) Descriptor centers of a pharmacophore corresponding to six-membered rings represented by. spheres in yellow, and nitrogen atoms represented by spheres in cyan, (c) Electrostatic potentials mapped onto an accessible surface. The more electronegative regions are colored in red, the more electropositive regions in blue...

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