Showing papers on "Pharmacophore published in 1991"

Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases.

Abstract: We have previously described a novel series of low molecular weight protein tyrosine kinase inhibitors which we named tyrphostins. The characteristic active pharmacophore of these compounds was the hydroxy-cis-benzylidenemalononitrile moiety. In this article we describe three novel groups of tyrphostins: (i) one group has the phenolic moiety of the cis-benzylidenemalononitrile replaced either with other substituted benzenes or with heteroaromatic rings, (ii) another is a series of conformationally constrained derivatives of hydroxy-cis-benzylidenemalononitriles in which the malononitrile moiety is fixed relative to the aromatic ring, and (iii) two groups of compounds in which the position trans to the benzenemalononitrile has been substituted by ketones and amides. Among the novel tyrphostins examined we found inhibitors which discriminate between the highly homologous EGF receptor kinase (HER1) and ErbB2/neu kinase (HER2). These findings may lead to selective tyrosine kinase blockers for the treatment of diseases in which ErbB2/neu is involved.

GABA-uptake inhibitors: construction of a general pharmacophore model and successful prediction of a new representative.

Abstract: A model for the pharmacophore of GABA-uptake inhibitors was established using published structure-activity data and molecular modeling. The model accounted for the activities of different classes of GABA-uptake inhibitors. Analogues of guvacine substituted at position 6 were synthesized in order to confirm the model. 6-(3,3-Di-phenylpropyl)guvacine (30f), which fit well with the pharmacophore, had an in vitro IC50 of 0.1 microM. This value is as good as those of the best GABA-uptake inhibitors known today.

Non-steroidal antiandrogens. Design of novel compounds based on an infrared study of the dominant conformation and hydrogen-bonding properties of a series of anilide antiandrogens.

Abstract: Antiandrogenic activity is observed in anilides containing a tertiary hydroxyl group, and these compounds are used to define a pharmacophore in terms of their physicochemical properties. Infrared spectroscopy shows that these anilides exist in a single conformation, which exerts a powerful influence on the hydrogen-bond donor ability of the hydroxyl group in a model system. Arguments are presented which suggest that hydrogen-bonding ability is an important contributor to biological activity. Compounds were synthesized that reproduced these properties in series not containing an amide bond. Such compounds were found to exhibit good antiandrogen activity. We suggest that quantitative information on hydrogen bonding might also be useful in other systems.

Modeling the cannabinoid receptor: a three-dimensional quantitative structure-activity analysis.

Abstract: The structure-activity relationship studies that have been reported for cannabinoids suggest that 1) the conformation of the C-ring at the C9 position, 2) the A-ring phenolic hydroxyl, and 3) the hydrophobic side chain are important determinants for the production of analgesia, as well as other cannabinoid effects. However, either these previous structure-activity studies described for cannabinoid compounds have not been quantitative in nature or the prediction of the activity of known and unknown compounds based on molecular structure has not been tested in a comprehensive manner. In this study we describe a three-dimensional molecular modeling program using comparative molecular field analysis to derive quantitative structure-activity relationships fitting pharmacological potencies and binding affinities of cannabinoids. The analysis has proven to accurately fit the pharmacological activity of cannabinoid analogs, with cross-validated r2 values of greater than 0.3 and final analysis r2 values of greater than 0.88. Additionally, this study has further characterized the steric and electrostatic properties that account for the variations in their potency. The results from this study indicate that steric repulsion behind the C-ring is associated with decreased predicted binding affinity and pharmacological potency. On the other hand, the steric bulk of a side chain that is extended up to seven carbons contributes to predictions of increased binding affinity and potency. The electrostatic fields of cannabinoid analogs also contribute to the predicted in vitro and in vivo potencies. If the biological activities we have investigated are assumed to be the result of interaction with a single binding site, this method indicates the structural and physicochemical properties necessary for binding to the receptor and producing an effect. By defining cannabinoid binding affinity and behavioral activity pharmacophores, this method can be used for designing cannabinoid agonists and it is capable of predicting the activity of unknowns, thereby serving to facilitate rational drug design.

A 3 dimensional model for 5-HT1A-receptor agonists based on stereoselective methyl-substituted and conformationally restricted analogs of 8-hydroxy-2-(dipropylamino)tetralin

Abstract: The enantiomers of cis- and trans-1,2,3,4,4a,5,10,10a-octahydro-9-hydroxy-1- propylbenzo[g]quinolines (10 and 11, respectively) and the enantiomers of trans-1,2,3,4,4a,5,6,10b-octahydro-10- hydroxy-4-propylbenzo[f]quinoline (12) have been synthesized and their stereochemical and conformational characteristics have been studied by use of X-ray crystallography and molecular mechanics (MMP2) calculations. The compounds, which are conformationally restricted analogues of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2- (dipropylamino)tetralin (8-OH-DPAT; 1) have been evaluated for central 5-HT and dopamine receptor stimulating activity by use of biochemical and behavioral tests in rats. In addition, we have evaluated the ability of these compounds and a number of previously reported analogues to displace [3H]-8-OH-DPAT from 5-HT1A-binding sites. The enantiomers of 12 behave as potent 5-HT1A-receptor agonists, whereas the octahydrobenzo[g]quinoline derivatives are much less potent or inactive. In general, the affinities of the compounds correlate well with their agonist potencies. The set of compounds under study is accommodated by a novel computer-graphics-derived model for 5-HT1A-receptor agonism. The model consists of a flexible pharmacophore and a partial receptor-excluded volume.

Structure/activity and molecular modeling studies of the lophotoxin family of irreversible nicotinic receptor antagonists.

Abstract: Lophotoxin is a small cyclic diterpene that irreversibly inhibits agonist binding to nicotinic acetylcholine receptors by reacting covalently with Tyr190 in the alpha-subunits of the receptor. Structure/activity and molecular modeling studies were undertaken to investigate the structural and conformational features responsible for this unique biological activity. A total of 18 naturally occurring and 7 chemically modified analogues were evaluated for their ability to inhibit the binding of [125I]-alpha-bungarotoxin to nicotinic acetylcholine receptors on membranes prepared from Torpedo electric organ. When the toxins were incubated with the receptor for short durations they did not slow the initial rate of binding of [125I]-alpha-bungarotoxin, suggesting that they have relatively low reversible affinity. However, their ability to inhibit the equilibrium binding of [125I]-alpha-bungarotoxin increased progressively with longer incubation times, consistent with an irreversible mechanism of action. Comparison of active and inactive analogues allowed identification of a conserved pharmacophore that appeared to be required for irreversible inhibition of the receptor. This pharmacophore contains lactone oxygens and an electron-deficient epoxide that may mimic the acetate oxygens and quaternary ammonium group of acetylcholine, respectively. Computer modeling of the toxins using molecular mechanics and dynamics revealed that the toxins have restricted conformational mobility, thus allowing identification of a minimum-energy conformation. The results allow speculation concerning the site of covalent reaction between Tyr190 and the toxins, the normal function of Tyr190 in binding acetylcholine, and the bound conformation of acetylcholine.

Novel indole-2-carboxylates as ligands for the strychnine-insensitive N-methyl-D-aspartate-linked glycine receptor.

Abstract: A series of indole-2-carboxylates were prepared and evaluated for their ability to inhibit the binding at the strychnine-insensitive glycine receptor that is associated with the NMDA-PCP-glycine receptor complex. All of the compounds were selective for the glycine site relative to other sites on the receptor macrocomplex and several of the compounds in this series were found to have submicromolar affinity for this receptor. The lead compound, 2-carboxy-6-chloro-3-indoleacetic acid (Ki = 1.6 microM vs [3H]glycine), was also found to noncompetitively inhibit the binding of MK-801, a ligand for the phencyclidine site on the receptor macrocomplex. These latter data suggest that the compound functions as an antagonist at the strychnine-insensitive glycine receptor. The structural activity relationships within this series of indole-2-carboxylates is discussed and several key pharmacophores are identified for this series of glycine ligands. In general, the most potent compounds were the C-3 acetamides, with N-propyl-2-carboxy-6-chloro-3-indoleacetamide having the highest receptor affinity.

Role of the spacer in conferring kappa opioid receptor selectivity to bivalent ligands related to norbinaltorphimine.

Abstract: The thiophene 2 and pyran 3 analogues of the kappa-selective opioid antagonist norbinaltorphimine (1a, norBNI) were synthesized and tested in an effort to determine the contribution of the spacer to the interaction of bivalent ligands at different opioid receptor types. Both 2 and 3 were found to be selective kappa opioid receptor antagonists in smooth muscle preparations, and they bound selectively to kappa-recognition sites. The thiophene analogue 2 displayed binding selectivity that was of the same order of magnitude as that of 1a, while 3 was considerably less selective for kappa site. This is consistent with the fact that the second pharmacophore in 1a and 2 displayed a greater degree of superposition than 1a and 3. The results of this study suggest that the pyrrole moiety of norBNI functions primarily as an inert spacer to rigidly hold the basic nitrogen in the second pharmacophore at an "address" subsite that is unique for the kappa opioid receptor.

Structure-activity relationships at 5-HT1A receptors: binding profiles and intrinsic activity.

Abstract: The 5-HT1A receptor has been one of the most studied 5-HT receptor subtypes in terms of its pharmacologic profile. Comparisons of various studies of structure-activity relationships (SAR) at this receptor shows an emerging profile for this receptor's pharmacophore. The present discussion focuses on the findings generated with relatively small molecules that can be considered as analogs of serotonin itself and that illustrate some of the structural properties that are important for high-affinity recognition by the receptor. Most of the SAR work has been based on the affinities of compounds for the receptor as determined by the radioligand-binding technique, which has a significant limitation in that it cannot define the intrinsic activity of compounds at the receptor. This problem can be addressed by functional assays, and an example of SAR at the 5-HT1A receptor-coupled adenylate cyclase system is provided.

The agonist pharmacophore of the benzodiazepine receptor. Synthesis of a selective anticonvulsant/anxiolytic.

Abstract: We wish to report the synthesis of a new anxiolytic/anticonvulsant, 6-(n-propoxy)-4-(methoxymethyl)-β-carboline-3-carboxylic acid ethyl ester (6-PBC, 1) which is devoid of myorelaxant and ataxic effects

Novel 1-phenylpiperazine and 4-phenylpiperidine derivatives as high-affinity sigma ligands.

Abstract: sigma receptors may represent an exciting new approach for the development of novel psychotherapeutic agents. Unfortunately, many of the commonly used sigma ligands lack selectivity (e.g., many bind at phencyclidine or dopamine receptors) or suffer from other serious drawbacks. Recently, we described a series of 2-phenylaminoethanes that bind at sigma receptors with high affinity and selectivity. Because there is evidence that 1-phenylpiperazines can structurally mimic the 2-phenylaminoethane moiety, we prepared a series of 1-phenylpiperazines and related analogues and incorporated structural features already shown to enhance the sigma binding of the 2-phenylaminoethanes. Several of these derivatives bind at sigma receptors with high affinity (Ki = 1-10 nM) and lack appreciable affinity for phencyclidine and dopamine receptors. In as much as certain of these agents structurally resemble the high-affinity, but nonselective, sigma ligand haloperidol, and because they bind with 10 times the affinity of haloperidol, we have apparently identified what appears to be the primary sigma pharmacophore of that agent.

Identification and exploitation of the sigma-opiate pharmacophore.

Abstract: Certain benzomorphan "sigma-opiates" such as N-allylnormetazocine (NANM) bind at sigma receptors with modest affinity and with little selectivity (i.e., they also bind at phencyclidine or PCP sites). In order to identify the primary pharmacophore of the benzomorphans, we prepared several amine-substituted derivatives of 1-phenyl-2-aminopropane. Several simple alkyl-substituted analogues were shown to bind at sigma sites with affinities comparable to that of NANM itself; among these was the N-benzyl derivative 9 (Ki = 117 nM). Lengthening the spacer between the terminal amine and the phenyl group from one to five methylene units resulted in a significant increase in affinity (e.g. 15, Ki = 6.3 nM). In addition, unlike the benzomorphans, these phenalkylamines do not bind at PCP sites. The results of the present study reveal that (a) the 1-phenyl-2-aminopropane nucleus of the benzomorphans is sufficient for binding at sigma sites provided that the terminal amine is not a primary amine and that (b) introduction of (phenylalkyl)amine substituents affords compounds that represent a new class of high-affinity sigma-selective agents.

Molecular modeling of 5-HT3 receptor ligands.

Abstract: Ligands of various chemical classes (e.g., indoles, indazoles, benzamides, carbazoles, and quinolines) have demonstrated high affinity for the 5-HT3 receptor in radiolabeled ligand-binding studies, and have shown 5-HT3 receptor antagonistic activity in functional assays which utilize the excitatory effects of 5-HT on enteric neurons and autonomic afferents. Several 5-HT3 antagonists are currently being evaluated for potential use in the treatment of migraine, schizophrenia, and anxiety, and a few have already demonstrated high efficacy as antiemetics in cancer chemotherapy. The purpose of this presentation is to highlight the significant structure-affinity relationships (SAFIR) and common geometrical features among 5-HT3 receptor ligands, and to describe the three-dimensional pharmacophore for the 5-HT3 recognition site derived from computational techniques. The chemical template containing the recognition elements (functional groups) for the 5-HT3 receptor are: an aromatic or heteroaromatic ring system, a coplanar carbonyl group, and a nitrogen center, interrelated by well-defined distances. Two "binding shapes" or "active shapes" for 5-HT3 ligands have been identified from detailed conformational analyses.

Identification of 5-hydroxytryptamine1A receptor agents using a composite pharmacophore analysis and chemical database screening.

Abstract: A composite pharmacophore analysis and computer-assisted chemical database screening were used to identify a previously unrecognized class of 5-hydroxytryptamine1A (5-HT1A) receptor active agents. An analysis of published data led to the identification of 20 different chemical structures which share nanomolar affinity for the 5-HT1A receptor. From a composite pharmacophore analysis of all 20 potent agents, we hypothesized that compounds containing a novel (in terms of 5-HT1A receptor analysis) 3 ring structure might be active at the 5-HT1A receptor. To test this hypothesis, the Chemical Abstracts database, which contains over 10 million compounds, was screened electronically for compounds that contain this core structure. A series of 319 agents was identified which contain this core structure. A total of 6 compounds was then obtained commercially and evaluated in radioligand binding studies. A single agent (Compound 69/183) conformed most closely to the composite 5-HT1A pharmacophore and displayed an affinity of 20 nmol/l for the 5-HT1A receptor binding site. Two other agents displayed affinities of 170 and 500 nmol/l, respectively, for the 5-HT1A receptor site. The 3 agents which differed most significantly from the composite 5-HT1A pharmacophore displayed affinities of 1,200− > 10,000 nmol/l for the 5-HT1A receptor binding site. These data suggest that a composite pharmacophore analysis and computer-assisted chemical database screening can be an effective technique for the identification of previously unrecognized receptor active agents.

trans-hexahydroindolo[4,3-ab]phenanthridines ("benzergolines"), the first structural class of potent and selective dopamine D1 receptor agonists lacking a catechol group.

Abstract: In contrast to the many selective dopamine (DA) D2 receptor agonists known, only two prototypes of selective D1 receptor agonists have been described; both show preference for the periphery due to their catechol partial structures. Our search for non-catechol, selective D1 agonists was based on the hypothesis that D1 selectivity could be conferred upon ergolines by annulation with a phenyl ring. The target molecules, trans-4,6,6a,7,8,12b-hexahydroindolo-[4,3-ab]phenanthridi nes ("benzergolines"), were efficiently synthesized by using the Ninomiya enamide photocyclization reaction. These compounds were found to be as active as the most potent D1 agonists in the adenylate cyclase D1 receptor model, but showed no activity in the ACh release D2 receptor assay. The acquired subtype selectivity of the novel structures was accompanied by an enhanced potency and efficacy as compared to the corresponding ergolines. This points to a D1 affinity enhancing, D2 receptor discriminating role for the additional phenyl group and provides further support for the existence of a D1 receptor specific accessory aryl binding site. Thus the benzergolines represent the first structural class of potent and selective D1 agonists lacking a catechol group which should allow an efficient central nervous system penetration. On the basis of these results, the D1 agonist pharmacophore has to be revised in the sense that potent activity requires neither a catechol function nor an orthogonal conformation of the aromatic rings.

The pharmacophore of debromoaplysiatoxin responsible for protein kinase C activation.

Abstract: Protein kinase C is physiologically activated by 1,2-diacyl-sn-glycerol in the S configuration. The enzyme is also powerfully activated by structurally diverse tumor promotors. A model has been developed that demonstrates how the various tumor promotors and diacylglycerols can all be accommodated by the same binding site of the kinase. One prediction of this model concerns the structural nature of the pharmacophore in the tumor promotor debromoaplysiatoxin. This prediction is realized by synthesizing the analogs with the deduced pharmacophore and demonstrating that they are potent activators of protein kinase C. These findings provide strong experimental support for our structural model of protein kinase C activation.

Comparative Molecular Field Analysis on a Set of Muscarinic Agonists

Abstract: A three-dimensional quantitative structure-activity relationship (3D-QSAR) was carried out on a set of 39 non-congeneric muscarinic agonists using Comparative Molecular Field Analysis (CoMFA) The compounds were tested on the M3 receptor subtype However, since most of these ligands are reported as unspecific muscarinic agents, the proposed pharmacophore model accounts for features common to all the receptor populations (M1, M2 and M3) In order to define an alignment rule for the superimposition of the ligands, a common pharmacophore frame was derived with a preliminary conformational search performed on four typical muscarinic agonists Both the steric and the electrostatic fields were used in CoMFA as molecular descriptors and were found relevant with almost the same statistical weight The CoMFA coefficient contour maps revealed consistency with our postulated mechanism of interaction Several 3D-QSARs were derived by means of the Partial Least Squares (PLS) method choosing the proper dimensionality with a cross-validation procedure

Clefts and binding sites in protein receptors.

Abstract: Publisher Summary This chapter discusses the methods for determining clefts and binding sites in protein receptors Direct methods of cleft determination are aimed at the analysis of a receptor whose three-dimensional structure is known The meaning of the term “protein surface” is discussed in the chapter so that all the methods can be related to a common set of definitions The different classes of algorithms that have been used to define and display the surface, to look at mappings of topographic features, to quantify surface roughness and curvature, and to search for packing defects and sites are reviewed in the chapter All these methods require a set of Cartesian coordinates and produce an essentially static picture of the receptor Biomolecules are dynamic objects and undergo substantial conformational changes; each static picture should, therefore, be regarded as a snapshot These stills should be combined into a moving trajectory or a partition function; this is implied whenever a new static method is introduced Indirect methods of receptor mapping are applicable when the receptor structure is unknown, but the structures of a series of ligands that bind to the receptor at a common site are available The binding site is deduced from the apparent common properties of the ligands—that is, the pharmacophore The assumptions behind pharmacophore deduction are discussed in the chapter The algorithms are illustrated in the chapter by case studies: the method of shape mapping is exemplified by a family of retinal isomers

Binding of substituted and conformationally restricted derivatives of N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane at sigma-receptors.

Abstract: Certain benzomorphans, such as N-allylnormetazocine, are classical "sigma-opiates" that bind both at sigma and phencyclidine (PCP) binding sites with modest affinity. Recently, we identified N-substituted 2-phenylaminoethane as being the primary sigma-pharmacophore of the benzomorphans and demonstrated that 1-phenyl-2-aminopropane (2) derivatives, depending upon their terminal amine substituents, constitute a novel class of high-affinity sigma-selective agents. With this pharmacophore, it is shown in the present investigation that the aromatic hydroxyl group (a prime feature of all the sigma-opiates) contributes little to the binding of 2 at sigma-sites. It is also demonstrated that an N-substituted aminotetralin moiety (such as 17, a conformationally restricted analogue of 2) may also be considered a sigma-opiate pharmacophore. Unlike the sigma-opiates, derivatives of 2 and 17 display no affinity for PCP sites and must consequently lack those structural features important for the binding of benzomorphans at PCP sites. Because 3-phenylpiperidines and related sigma-ligands also possess a phenylalkylamine imbedded within their structures, we propose that the 2-phenylaminoethane moiety is a common sigma-pharmacophore for derivatives of 2, the 3-phenylpiperidines, and the sigma-opiates.

Theoretical Determination of the Putative Receptor-bound Conformations of 5-HT2 Receptor Agonists†

Abstract: For a series of compounds with agonistic activity at the 5-HT2 receptor a pharmacophoric model was established. It has been shown by means of conformational analyses and molecular electrostatic potential calculations that the pharmacophores of all active compounds can adopt common positions at the receptorsite. Besides our model offers an explanation for the stereoselectivity of the chiral compounds as well as for the complete loss of activity of a phenylethylamine compound containing an α,α-dimethyl sidechain.

Conformational properties of semirigid antipsychotic drugs: the pharmacophore for dopamine D-2 antagonist activity.

Abstract: Conformational energy calculations using the MM2-87 program have been performed on the tetracyclic spiro amines 1 (A23887) and 2 (A31472) which have previously been shown to have considerable affinity for dopamine D-2 receptors. These compounds are important for defining the pharmacophore for D-2 antagonist activity due to their limited conformational freedom. Possible foldings of the multicyclic structure were energy minimized and the barriers for inversion and for rotation of the ammonium group were computed. The conformational properties of 1 and 2 are consistent with a pharmacophore recently proposed by Liljefors and Bogeso. The greater affinity of (S)-octoclothepin for D-2 receptors as compared with its enantiomer was attributed to the latter having an incorrect orientation of the ammonium hydrogen despite the correct folding of the tricyclic structure. Other D-2 antagonists with limited conformational freedom such as butaclamol, isobutaclamol, loxapine, clozapine, and resolved cyproheptadine analogues were also found to be consistent with the pharmacophore. In addition, 1, 2, and their enantiomers were tested on radioligand binding assays for dopamine D-1, dopamine D-2, noradrenergic alpha-1, serotonergic 5-HT2, muscarinic, and sigma receptors. 1 and 2 have greater affinities than their enantiomers in the D-1, D-2, alpha-1, and 5-HT2 assays though there was little difference between 2 and its enantiomer in the latter two assays. In the muscarinic assays, 2 and its enantiomer, which were approximately equipotent, had greater affinity than 1 and its enantiomer. None of the compounds had substantial affinity for sigma receptors. Since the same enantiomers of 1, 2, butaclamol, and the resolved cyproheptadine analogues also have greater affinities for D-1 receptors, the conformational requirements of D-1 ligands appear to be quite similar to those of D-2 ligands.

Non‐Steroidal Antiandrogens. Design of Novel Compounds Based on an Infrared Study of the Dominant Conformation and Hydrogen‐Bonding Properties of a Series of Anilide Antiandrogens.

Abstract: Antiandrogenic activity is observed in anilides containing a tertiary hydroxyl group, and these compounds are used to define a pharmacophore in terms of their physicochemical properties. Infrared spectroscopy shows that these anilides exist in a single conformation, which exerts a powerful influence on the hydrogen-bond donor ability of the hydroxyl group in a model system. Arguments are presented which suggest that hydrogen-bonding ability is an important contributor to biological activity. Compounds were synthesized that reproduced these properties in series not containing an amide bond. Such compounds were found to exhibit good antiandrogen activity. We suggest that quantitative information on hydrogen bonding might also be useful in other systems.

Chapter 29. Receptor Modeling by Distance Geometry

Abstract: Publisher Summary Distance geometry is a general molecular model-building method known for determining the three-dimensional solution structures of peptides, proteins, and nucleic acids from nuclear overhauser effect (NOE) distance measurements. It has also been applied to the models of proteins and receptors and the interaction of small molecules with the receptors. A recently published comprehensive review of distance geometry and its application to receptor modeling emphasizes their distance geometry quantitative structure–activity relationship (QSAR) approaches. This chapter discusses the additional distance geometry approaches that have application in receptor modeling and distance geometry QSAR method, protein structure modeling, drug receptor docking, and pharmacophore modeling using the ensemble approach. Crippen applied distance geometry to the problem of three-dimensional receptor mapping. Ghose and Crippen have reviewed the approach in detail. Ghose and Crippen's method proposed the geometric requirements of the receptor site based on the experimental data of binding affinities of a series of ligands that may be conformationally flexible and may be hypothesized binding modes for each ligand. The result was a low-resolution, three-dimensional model of the receptor binding site, which was described as a series of points in space (site points) that interact with specific ligand atoms or groups of atoms (ligand points). Each ligand point was described by atom-centered physicochemical properties (molar refractivity, hydrophobicity, and partial charge). A specific interaction energy was assigned to each site point—ligand point interaction by a modified quadratic programming optimization procedure—yielding a quantitative prediction of the binding affinity of each ligand to the site model. The chapter discusses Voronoi binding site models. Distance geometry software is now more readily available, along with a steadily increasing number of applications and publications that demonstrate molecular models involving drug–receptor docking, pharmacophore modeling, protein structure prediction, and conformational analysis.