Different approaches toward an automatic structural alignment of drug molecules: Applications to sterol mimics, thrombin and thermolysin inhibitors

Abstract

A relative comparison of the binding properties of different drug molecules requires their mutual superposition with respect to various alignment criteria. In order to validate the results of different alignment methods, the crystallographically observed binding geometries of ligands in the pocket of a common protein receptor have been used. The alignment function in the program SEAL that calculates the mutual superposition of molecules has been optimized with respect to these references. Across the reference data set, alignments could be produced that show mean rms deviations of approximately 1 A compared to the experimental situation. For structures with obvious skeletal similarities a multiple-flexible fit, linking common pharmacophoric groups by virtual springs, has been incorporated into the molecular mechanics program MOMO. In order to combine conformational searching with comparative alignments, the optimized SEAL approach has been applied to sets of conformers generated by MIMUMBA, a program for conformational analysis. Multiple-flexible fits have been calculated for inhibitors of ergosterol biosynthesis. Sets of different thrombin and thermolysin inhibitors have been conformationally analyzed and subsequently aligned by a combined MIMUMBA/SEAL approach. Since for these examples crystallographic data on their mutual alignment are available, an objective assessment of the computed results could be performed. Among the generated conformers, one geometry could be selected for the thrombin and thermolysin inhibitors that approached reasonably well the experimentally observed alignment.

Strategies for the design of inhibitors of aldose reductase, an enzyme showing pronounced induced-fit adaptations

“…This dualscoring problem does not make the problem simpler; even so, the strategy appears very convincing. We have focussed on another alternative which takes advantage of the successful superpositioning of ligand molecules according to their spatial similarity in terms of physicochemical properties [O. Krämer, Dissertation, University of Marburg, 2003] [36,37]. In previous studies, we have applied the program SEAL [38] to produce reasonable ligand alignments as a prerequisite for subsequent comparative molecular field analysis (CoMFA) [39] and comparative molecular similarity indices (CoM-SIA) [40].…”

Non‐thiol Farnesyltransferase Inhibitors: Utilization of the Far Aryl Binding Site by 5‐Cinnamoylaminobenzophenones

“…Flexible docking was performed using FlexX [24] version 1.11. During ligand construction, the FlexX command MAPREF and the perturbate algorithm was used for the placement of the base fragment.…”

“…Flexible docking was performed using the program FlexX [24]. Based on the coordinates of the published crystal structure [25] of a ternary complex of farnesyltransferase, a farnesylpyrophosphate analog, and Nacetyl-Cys-Val-Ile-selenoMetOH (PDB-code 1QBQ), we have calculated the solvent-accessible surface of the farnesyltransferase active site using the program MOLCAD as implemented in the molecular modeling software package SYBYL [26].…”

Exploring the activity space of peptides binding to diverse SH3 domains using principal property descriptors derived from amino acid rotamers

“…The minimized single conformation of Ala (which has no rotamers but possesses a side-chain beta C atom) was adopted here as template and other 18 rotamer assemblies (except Gly) were in turn superposed on it using atomic root-mean-square (RMS) fitting method. 32 Only the four backbone atoms were considered when superposing Gly onto Ala template. The superposition result is as shown in Figure 3.…”