The Use of the GRID Program in the 3-D QSAR Analysis of a Series of Calcium-Channel Agonists

Abstract

The use of GRID in the 3-D QSAR analysis of a series of calcium-channel agonists is described. Partial least-squares analysis of GRID maps showing the interaction energy between an alkyl hydroxyl probe and a series of agonists in 3-D space generated a predictive quantitative model of the variation of biological activity. The macroscopic descriptors CLOGP and CMR were included in the analysis, and the importance of appropriate block scaling is highlighted. The discussion highlights the interpretation of the resulting regression maps, and the steric, electrostatic, lipophilic, and hydrogen-bonding preferences of the calcium-channel receptor are identified.

From Hansch‐Fujita Analysis to AFMoC: A Road to Structure‐Based QSAR

“…Rather, as shown for a data set of 79 thrombin inhibitors and three structurally diverse protein models, the AFMoC con approach led to a QSAR model the internal and external predictivity of which was comparable to the best model derived from a standard AFMoC run 25. As to the regression technique, AFMoC con applies partial least‐squares regression considering multimode binding (MMB)26 and a variable influence on the model(VINFM)‐based region selection27 to an extended descriptor matrix (Figure 2). After an initial PLS analysis considering MMB and a VINFM‐based variable selection, a consensus descriptor matrix is generated and subjected to another PLS analysis considering MMB.…”

Optimising the EVA descriptor for prediction of biological activity

“…1 The intention of the present study is to illustrate the application of the method to biological data that are within the public domain, incidentally providing a comparison of the performance of the EVA descriptor with that of other, more familiar, descriptors. A convenient example lies in a set of calcium ion channel agonists and their associated responses in an assay of biological activity; 4 this represents a particularly attractive set as it has been analysed previously by Davis et al 5,6 with another theoretically-based 3-D descriptor, GRID. 7 This paper compares the performance of EVA with the published results of this study.…”

“…In the previous work, 5,6 the 3D structural descriptor, GRID, 7 was used to analyse the molecular features which account for the observed activities. The additional inclusion of selected physicochemical descriptors, and the consequences of variable scaling, was then considered in turn to assess whether the QSAR model could be improved upon.…”

“…Table 1 shows the structures of the compounds used by Davis et al 5,6 The compounds were assayed in vitro for their inotropic potency, i.e., their ability to increase cardiac contractibility, using guinea pig atria paced at 1 Hz. This was expressed as the concentration of the drug that increased the tension developed in the preparation to 50% of the isoprenaline maximum (EC 50 ).…”

Novel Hantzsch 1,4-dihydropyridines to study the structure-function relationships of calcium channels and photoinduced relaxation

“…In contrast, DHP CC agonists [positive inotropes] offer a potentially new approach to drug discovery targeted toward the treatment of congestive heart failure (CHF), and as probes to study the structure-function relationships of L-type calcium channels (Vo et al, 1995]. DHP compounds such as the nitro analogs Bay K 8644 [Schramm et al, 1983], (+)-(S)-PN 202-791 [Hof et al, 1985], and the (RR)-diastereomer of LY249933 [Holland et al, 1989], lactone CGP 28392 DRUG DEVELOPMENT RESEARCH 42:120-130 (1997) [Erne et al, 1984], 5-unsubstituted H 160/51 [Beyer et al, 1985;Gjorstrup et al, 1986], amide YC 170 [Takenaka and Maeno, 1983;Takeda, 1993], dicarboxylic acid ester [Sunkel et al, 1992], and benzoylpyrrole FPL 64176 [Baxter et al, 1993;Davis et al, 1994] exhibit CC agonist activity (see Fig. 1 for structures).…”