Three‐Dimensional Quantitative Structure‐Activity Relationships I. General Approach to the Pharmacophore Model Validation

Abstract

A conceptually and computationally integrated approach to pharmacophore model validation is discussed at length. It allows one, for the first time, to address the question of pharmacophore existence and assessment of its uniqueness in a rigorous and quantitative manner. The approach has been effectively applied to the analysis of seventeen structurally diverse potent inhibitors of angiotensin converting enzyme and the resultant pharmacophore greatly refines the previously suggested models.

New methods in computer-aided drug design

“…ROBERT P. SHERIDAN 21,1987) In trod uction Pharmaceutical research has been successful in identifying therapeutic agents by using conventional screening techniques. In this approach, large numbers of randomly selected compounds, either natural products or synthesized compounds, are tested in a battery of biological assays, or "screens".…”

Three‐Dimensional Quantitative Structure‐Activity Relationships. 2. Conformational Mimicry and Topographical Similarity of Flexible Molecules

“…Maximin requires characterization of molecular topography (a set of Cartesian coordinates defining the equilibrium position of constituent atoms), molecular topology (a table of atom connectivities), and chemical constitution (a list of atom and bond types); a virtual atom type, Du ("dummy"), three different methods for performing geometry optimization are provided: (i) Optimization on atom-by-atom basis: the corrections to the coordinate triple of atoms which do not belong to aggregate (see [12]) are optimized simultaneously. (ii) Optimization of the orientation of molecular fragments, which are treated as rigid entities ("aggregates"), by rotations and translations with respect to the axes of the Cartesian reference system.…”

“…Topological methods [33 -351 to estimate the degree of similarity between chemical structures are applicable to essentially conformationally rigid molecules. Evidently, explicit consideration of the conformational variable requires a topographical approach to the problem of molecular similarity [36-381. Conformational mimicry of molecules is intimately related to the problem of existence of a consistent pharma-cophore model [12] for the molecules under study. In the absence of any molecular information concerning the biological receptor, a consistent pharmacophore model can be regarded as a topographical and physico-chemical specification of the receptor, and allows meaningful comparison of the topography of structurally diverse molecules exhibiting the same biological action; therefore, it provides an appropriate basis from which to compute 3D-QSAR, or quantitative three-dimensional receptor maps [38].…”

“…Calculations of energy and geometrical features of complex molecular systems (illustrative examples are provided by studies [l -61 of the interaction of u-chymotrypsin with various substrates) are usually performed using molecular mechanics methods [7 -111. The paper is complementary to Paper 1, ref. [12], and presents our molecular mechanics program (Maximin): we emphasize here the distinctive features which make Maximin extremely suitable for determination of the existence of consistent pharmacophore models, assessment of conformational mimicry and determination of the topographical similarities of flexible molecules. The paper is organized as follows: Sect.…”

Structure‐Based Calculation of Binding Affinities of α2A‐Adrenoceptor Agonists

“…The structures of the 15 agonist molecules (noradrenaline, a-methyl-noradrenaline, B-HT 920, brimonidine, clonidine, dexmedetomidine, guanabenzamidine, guanfacine, levlofexidine, oxymetazoline, p-aminoclonidine, rilmenidine, st91, xylometazoline, and a54741) were built, optimized, and supplied with Gasteiger charges by using the SYBYL program package and force field. [42][43][44] The docking box with 22.5 22.5 22.5 3 volume was centered at the binding region known from site-directed mutagenesis studies. [6] All docking calculations were performed as in Ref.…”