Showing papers on "Pharmacophore published in 1998"

FlexS: A Method for Fast Flexible Ligand Superposition

Abstract: If no structural information about a particular target protein is available, methods of rational drug design try to superimpose putative ligands with a given reference, e.g., an endogenous ligand. The goal of such structural alignments is, on the one hand, to approximate the binding geometry and, on the other hand, to provide a relative ranking of the ligands with respect to their similarity. An accurate superposition is the prerequisite of subsequent exploitation of ligand data by either 3D QSAR analyses, pharmacophore hypotheses, or receptor modeling. We present the automatic method FLEXS for structurally superimposing pairs of ligands, approximating their putative binding site geometry. One of the ligands is treated as flexible, while the other one, used as a reference, is kept rigid. FLEXS is an incremental construction procedure. The molecules to be superimposed are partitioned into fragments. Starting with placements of a selected anchor fragment, computed by two alternative approaches, the remaining fragments are added iteratively. At each step, flexibility is considered by allowing the respective added fragment to adopt a discrete set of conformations. The mean computing time per test case is about 1:30 min on a common-day workstation. FLEXS is fast enough to be used as a tool for virtual ligand screening. A database of typical drug molecules has been screened for potential fibrinogen receptor antagonists. FLEXS is capable of retrieving all ligands assigned to platelet aggregation properties among the first 20 hits. Furthermore, the program suggests additional interesting candidates, likely to be active at the same receptor. FLEXS proves to be superior to commonly used retrieval techniques based on 2D fingerprint similarities. The accuracy of computed superpositions determines the relevance of subsequently performed ligand analyses. In order to validate the quality of FLEXS alignments, we attempted to reproduce a set of 284 mutual superpositions derived from experimental data on 76 protein-ligand complexes of 14 proteins. The ligands considered cover the whole range of drug-size molecules from 18 to 158 atoms (PDB codes: 3ptb, 2er7). The performance of the algorithm critically depends on the sizes of the molecules to be superimposed. The limitations are clearly demonstrated with large peptidic inhibitors in the HIV and the endothiapepsin data set. Problems also occur in the presence of multiple binding modes (e.g., elastase and human rhinovirus). The most convincing results are achieved with small- and medium-sized molecules (as, e.g., the ligands of trypsin, thrombin, and dihydrofolate reductase). In more than half of the entire test set, we achieve rms deviations between computed and observed alignment of below 1.5 A. This underlines the reliability of FLEXS-generated alignments.

Synthesis and biological activity of a novel series of nonsteroidal, peripherally selective androgen receptor antagonists derived from 1,2-dihydropyridono[5,6-g]quinolines.

Abstract: A new nonsteroidal antiandrogenic pharmacophore has been discovered using cell-based cotransfection assays with human androgen receptor (hAR). This series of AR antagonists is structurally characterized by a linear tricyclic 1,2-dihydropyridono[5,6-g]quinoline core. Analogues inhibit AR-mediated reporter gene expression and bind to AR as potently as or better than any known AR antagonists. Several analogues also showed excellent in vivo activity in classic rodent models of AR antagonism, inhibiting growth of rat ventral prostate and seminal vesicles, without accompanying increases in serum gonadotropin and testosterone levels, as is seen with other AR antagonists. Investigations of structure−activity relationships surrounding this pharmacophore resulted in molecules with complete specificity for AR, antagonist activity on an AR mutant commonly observed in prostate cancer patients, and improved in vivo efficacy. Molecules based on this series of compounds have the potential to provide unique and effective ...

Structure-based design of enzyme inhibitors and receptor ligands.

Abstract: With the ongoing progress in protein crystallography and NMR, structure-based drug design is adopting increasing importance in the search for new drugs. Modeling starts from the 3D structure of a target protein in order to construct molecules which are complementary to a binding site, in their geometry as well as in the pattern of their physicochemical properties around the molecules. The rational design process is accompanied by 3D structure determinations of different ligand-protein complexes. Most often, significantly improved binding affinities of the ligands are observed after several cycles of 3D structure determinations, the design of compounds with appropriate structural modifications, synthesis, and testing of the new drug candidates. As an alternative, pharmacophore models are derived from the 3D structures of active analogs. A risk with lead structure optimization by structure-based design is the neglect of other important biological properties, such as bioavailability and metabolic stability. Recent applications of structure-based design, as well as success stories in the search for new, potent and selective HIV protease inhibitors, thrombin inhibitors, neuraminidase inhibitors and integrin receptor antagonists, are reviewed.

Melatonin Receptor Ligands: Synthesis of New Melatonin Derivatives and Comprehensive Comparative Molecular Field Analysis (CoMFA) Study

Abstract: The CoMFA methodology was applied to melatonin receptor ligands in order to establish quantitative structure-affinity relationships. One hundred thirty-three compounds were considered: they were either collected from literature or newly synthesized in order to gain information about the less explored positions. To this end, various melatonin derivatives were prepared and their affinity for quail optic tecta melatonin receptor was tested. Compounds were aligned on the putative active conformation of melatonin proposed by our previously reported pharmacophore search, and their relative affinities were calculated from the displacement of 2-[125I]-iodomelatonin on different tissues expressing aMT receptors. Compounds were grouped into three sets according to their topology. Subset A: melatonin-like compounds; subset B: N-acyl-2-amino-8-methoxytetralins and related compounds; subset C:N-acyl-phenylalkylamines and related compounds. CoMFA models were derived for each set, using the steric, electrostatic, and lipophilic fields as structural descriptors; the PLS analyses were characterized by good statistical parameters, taking into account the heterogeneity of the binding data, obtained with different experimental protocols. From the CoMFA model for the melatonin-like compounds, besides the well-known positive effect of 2-substitution, a low steric tolerance for substituents in 1, 6, and 7, and a negative effect of electron-rich 4-substituents were observed; the information provided by the newly synthesized compounds was essential for these results. Moreover, a comprehensive model for the 133 compounds, accounting for a common alignment and a common mode of interaction at the melatonin receptor, was derived (Q2 = 0.769, R2 = 0.905). This model validates our previously reported pharmacophore search and offers a clear depiction of the structure-affinity relationships for the melatonin receptor ligands.

Design, synthesis, and biological activities of new thieno[3,2-d] pyrimidines as selective type 4 phosphodiesterase inhibitors.

Abstract: A common pharmacophore for compounds structurally related to nitraquazone has been derived. Using this pharmacophore, new structures have been designed, synthesized, and evaluated for their inhibitory potencies against cyclic adenosine 5'-monophosphate (cAMP) specific phosphodiesterase (PDE 4). From these compounds, 4-benzylamino-2-butylthieno[3,2-d]pyrimidine (4) was selected for optimization. The effects of changes to the lipophilic groups and the amino linkage on the PDE 4 activity have been investigated. As a result, some potent PDE 4 inhibitors, selective with respect to PDE 3, have been identified. A selected group of compounds have been further evaluated for their ability to displace [3H]rolipram from its binding site and also to potentiate isoprenaline-induced cAMP accumulation in isolated guinea pig eosinophils. Of these, 2-butyl-4-cyclohexylaminothieno[3,2-d]pyrimidine (33) has an interesting profile, with an important improvement in PDE 4/[3H]rolipram ratio with respect to reference drugs, and good activity in cAMP potentiation, consistent with efficient cell penetration.

Pharmacophoric Requirements for Cannabinoid Side Chains: Multiple Bond and C1‘-Substituted Δ8-Tetrahydrocannabinols

Abstract: Accumulated evidence indicates that within the cannabinoid structure the aliphatic side chain plays a pivotal role in determining cannabimimetic activity. We describe the synthesis and affinities for the CB1 and CB2 receptors of a series of novel Δ8-THC analogues in which the side-chain pharmacophores are conformationally more defined than in the parent molecule. No analogue has the side-chain pharmacophore in a fully restricted conformation. However, our design serves to narrow down the scope of options for conformational requirements at the receptor active sites. All the analogues tested showed nanomolar or subnanomolar affinities for the receptors; 2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-hydroxy-6H-dibenzo[b,d]pyranyl)-2-hexyl-1,3-dithiolane was found to possess very high affinity for both cannabinoid receptors (CB1, Ki = 0.32 nM; CB2, Ki = 0.52 nM).

Derivation of a pharmacophore model for anandamide using constrained conformational searching and comparative molecular field analysis.

Abstract: Constrained molecular dynamics simulations on anandamide, together with a systematic distance comparison search, have revealed a specific low-energy conformer whose spatial disposition of the pharmacophoric elements closely matches that of HHC. This conformer enables near superposition of the following: (1) the oxygen of the carboxyamide and the phenolic hydroxyl group of HHC, (2) the hydroxyl group of the ethanol and the cyclohexyl hydroxyl group of HHC, (3) the alkyl tail and the lipophilic side chain of HHC, and (4) the polyolefin loop and the tricyclic ring structure of HHC. The close matching of common pharmacophoric elements of anandamide with HHC offers persuasive evidence of the biological relevance of this conformer. The proposed pharmacophore model was capable of discriminating between structurally related compounds exhibiting different pharmacological potency for the CB1 cannabinoid receptor, i.e., anandamide and N-(2-hydroxyethyl)prostaglandinamide. Furthermore, a 3D-QSAR model was derived us...

C16 and C17 derivatives of estradiol as inhibitors of 17 beta-hydroxysteroid dehydrogenase type 1: chemical synthesis and structure-activity relationships.

Abstract: As a first part of our research focused on the synthesis of 17 beta-HSD type 1 inhibitors without estrogenic activity, we needed to identify a small, easy-to-handle pharmacophore able to block the enzymatic activity. Previous studies on the active site of the enzyme by affinity labeling gave us a basis for the design of steroidal inhibitors derivatives. Several estradiol derivatives bearing a short (three carbons) side chain in position 17 alpha or 16 alpha were synthesized and tested for their ability to inhibit the transformation of estrone into estradiol by 17 beta-HSD type 1 (cytosolic fraction of human placenta). We found that 16 alpha-derivatives of estradiol gave better 17 beta-HSD inhibition than their corresponding 17 alpha analogs. Among several chemical groups used in this study, we conclude that better 17 beta-HSD inhibition was obtained for compounds with a good leaving group at the end of side chain. Thus, an iodopropyl or a bromopropyl side chain at C16 alpha of estradiol (E2) inhibit efficiently the 17 beta-HSD type 1 with IC50 values of 0.42 and 0.46 microM, respectively. Their 17-keto analogs inhibit also the enzyme activity similarly. Since this kind of compounds inhibit the 17 beta-HSD type 1 in time-dependent manner and that enzymatic activity cannot be restored later, we conclude to inhibitor of inactivator type. This conclusion is in accordance with the correlation observed between the ability of leaving group to dissociate and their potency to inhibit 17 beta-HSD type 1. We have also observed that additional addition of untritiated estrone protect the enzyme against the inactivation caused by 16 alpha-bromopropyl-E2 suggesting a competitive inhibitor of 17 beta-HSD. The bromopropyl pharmacophore was then selected to be further added onto an antiestrogenic steroid nucleus.

Classical/Nonclassical Hybrid Cannabinoids: Southern Aliphatic Chain-Functionalized C-6β Methyl, Ethyl, and Propyl Analogues

Abstract: The stereoelectronic requirements for interaction of the southern aliphatic hydroxyl of cannabimimetic pharmacophores with the CB1 and CB2 receptors are explored. The stereoselective syntheses of three series of classical/nonclassical hybrid cannabinoids are described. These compounds were designed to investigate the importance of the southern aliphatic hydroxyl (SAH) pharmacophore for cannabimimetic activity. Variation in the chain length of the SAH moiety in these 6β-(hydroxyalkyl)dihydrobenzopyran analogues, from 6β-hydroxymethyl to 6β-(ω-hydroxyethyl) and 6β-(ω-hydroxypropyl), and the effects of replacing the hydroxyl functionality by hydride and iodide are reported. Our results indicate that the SAH pharmacophore has less pronounced effects than the C-3 aliphatic chain on cannabinoid activity. Furthermore, it appears that this southern molecular component is capable of interacting with two different subsites on the receptor and that the nature of this interaction is determined by the terminal substit...

De Novo Design, Synthesis, and Biological Activities of High-Affinity and Selective Non-Peptide Agonists of the δ-Opioid Receptor‖

Abstract: On the basis of the structure−activity relationships of δ-opioid-selective peptide ligands and on a model of the proposed bioactive conformation for a potent and selective, conformationally constrained δ-opioid peptide ligand [(2S,3R)-TMT1]DPDPE, a series of small organic peptide mimetic compounds targeted for the δ-opioid receptor have been designed, synthesized, and evaluated in radiolabeled ligand binding assays and in vitro bioassays. The new non-peptide ligands use piperazine as a template to present the most important pharmacophore groups, including phenol and phenyl groups and a hydrophobic moiety. This hydrophobic group was designed to mimic the hydrophobic character of the d-Pen residues in DPDPE, which has been found to be extremely important for increasing the binding affinity and selectivity of these non-peptide ligands for the δ-opioid receptor over the μ-opioid receptor. Compound 6f (SL-3111) showed 8 nM binding affinity and over 2000-fold selectivity for the δ-opioid receptor over the μ-opi...

PrGen: Pseudoreceptor Modeling Using Receptor‐mediated Ligand Alignment and Pharmacophore Equilibration

Abstract: Based on the structures of known ligand molecules, a pseudoreceptor modeling concept developed at our laboratory allows the construction of a peptidic binding-site model for a structurally uncharacterized bioregulator. Such a three-dimensional receptor surrogate — validated using an external set of test compounds — should be able to semi-quantitatively predict the binding affinities of related molecules. To reduce problems resulting from the mutual obscuring of functional groups within a pharmacophore hypothesis, we have devised a procedure referred to as receptor-mediated ligand alignment. It permits to identify an alternate position, orientation and conformation for each ligand molecule by means of conformational search within a primordial receptor model, constructed about the most potent ligands of a series. To derive an energetically relaxed model with a high correlation between calculated and experimental free energies of ligand binding, we have developed a ligand equilibration protocol. During this iterative procedure, the receptor surrogate and the pharmacophore are allowed to relax individually, with and without correlation-coupled energy minimization, respectively, until a high correlation is achieved in a relaxed state. In our approach (software PrGen), free energies of ligand binding are estimated based on ligand-pseudoreceptor interactions using a directional force field, ligand desolvation energy and the change of both ligand-internal energy and ligand entropy upon receptor binding. The concept was tested by generating and evaluating a pseudoreceptor for the cannabinoid receptor. The binding-site surrogate for this system was constructed about a pharmacophore comprising 18 cannabinoid antagonists. It consists of 26 amino-acid residues and is capable of predicting free energies of ligand binding, ΔG°, for an external set of 10 test molecules to within 0.8 kcal/mol (RMS) of their experimental value, corresponding to an uncertainty factor of 4 in the binding affinity. Maximal individual errors of predicted binding affinities do not exceed a factor of 12.

Designing bioactive molecules : three-dimensional techniques and applications

Abstract: Three-dimensional structural information often provides the key to discovering or designing bioactive molecules and compounds. This volume covers the principal computational techniques for processing three-dimensional structures of small molecules and compounds. It describes database construction and searching, analysis of structure-activity relationships by pharmacophore mapping and QSAR, prediction of biological potency of small molecules and compounds by QSAR and by docking to macromolecular targets. The book also includes a chapter on de novo design of ligands to fit a macromolecular target.

5-HT3 Antagonists Derived from Aminopyridazine-type Muscarinic M1 Agonists

Abstract: A conformational analysis, performed on muscarinic M1 agonists, identified four structural features characteristic of the muscarinic M1 pharmacophore: (i) a protonable basic or quaternary nitrogen acting as a cationic head; (ii) an electronegative dipole usually part of a planar mesomeric ester, amide, or amidine function which can be replaced by an ether (muscarine) or a dioxolane (AF 30); (iii) an intercharge distance of 5 ± 0.5 A between the cationic head and the electronegative atom of the dipole; (iv) an elevation of 0.5 ± 0.03 A of the cationic head over the plane containing the electronegative dipole. During a reinvestigation of the conformational behavior of published structures of 5-HT3 antagonists, similar features were observed for the 5-HT3 pharmacophore. However many 5-HT3 antagonists possess additional aromatic planes not present in the muscarinic M1 agonists. These observations brought us to predict the chemical modifications that would change muscarinic M1 agonists into 5-HT3 antagonists....

Discovery of a Novel Series of Potent and Selective Substrate-Based Inhibitors of p60c-src Protein Tyrosine Kinase: Conformational and Topographical Constraints in Peptide Design§

Abstract: On the basis of the efficient substrate for p60c-src protein tyrosine kinase (PTK) YIYGSFK-NH2 (1) (Km = 55 μM) obtained by combinatorial methods, we have designed and synthesized a series of conformationally and topographically constrained substrate-based peptide inhibitors of this enzyme, which showed IC50 values in the low-micromolar range (1−3 μM). A “rotamer scan” was performed by introducing the four stereoisomers of β-Me(2‘)Nal in the postulated interaction site of the peptide inhibitor 23 (IC50 = 1.6 μM). This substitution led to selective and potent inhibitors of p60c-src PTK; however, no substantial difference in potency was observed among them. This and the results of the “stereochemical scan” performed at residues 2 and 7 of 3 (peptides 19−21), which form the disulfide bond, may suggest that the enzyme active site does not have rigid topographic requirements and thus is able to achieve important conformational changes to bind the ligand as long as the pharmacophore pattern in the inhibitor is ...

Pharmacophoric Search and 3D-QSAR Comparative Molecular Field Analysis Studies on Agonists of Melatonin Sheep Receptors

Abstract: Conformational analysis was used to characterize the agonist pharmacophore for melatonin sheep brain receptor recognition and activation. The molecular geometry shared by all conformations of the selected active ligands was determined. Assuming that all the compounds interact at the same binding site at the receptor level, 2-iodomelatonin pharmacophoric conformation served as a template for the superimposition of 64 structurally heterogeneous agonists constituting the training set used to perform a three-dimensional quantitative structure-activity relationship study via the comparative molecular field analysis method. A statistically significant model was obtained for the totality of the compounds (n = 64, q2 = 0.62, N = 6, r2 = 0.96, s = 0.28, F = 249) with steric, electrostatic, and lipophilic relative contributions of 28%, 35%, and 37%, respectively. The predictive power of the proposed model was discerned by successfully testing the 78 agonist ligands constituting the test set. The model so obtained and validated brings important structural insights to aid the design of novel melatoninergic agonist ligands prior to their synthesis.

Synthesis and Evaluation of Analogues of the Partial Agonist 6-(Propyloxy)-4-(methoxymethyl)-β-carboline-3-carboxylic Acid Ethyl Ester (6-PBC) and the Full Agonist 6-(Benzyloxy)-4-(methoxymethyl)-β- carboline-3-carboxylic Acid Ethyl Ester (Zk 93423) at Wild Type and Recombinant GABAA Receptors

Abstract: A pharmacophore and an alignment rule have previously been reported for BzR agonist ligands The design and synthesis of 6-(propyloxy)-4-(methoxymethyl)-β-carboline-3-carboxylic acid ethyl ester (6-PBC, 24, IC50 = 81 nM) was based on this pharmacophore When evaluated in vivo this ligand exhibited anticonvulsant/anxiolytic activity but was devoid of the muscle relaxant/ataxic effects of “classical” 1,4-benzodiazepines (ie, diazepam) Significantly, 6-PBC 24 also reversed diazepam-induced muscle relaxation in mice The 3-substituted analogues 40−46 and 48 of 6-PBC 24 and Zk 93423 27 (IC50 = 1 nM) were synthesized and evaluated in vitro to determine what affect these modifications would have on the binding affinity at recombinant BzR subtypes With the exception of the 3-amino ligands 40 and 41, all the β-carbolines were found to exhibit high binding affinity at BzR sites The 3-propyl ether derivative 45 was also evaluated in vivo and found to be devoid of any proconvulsant or anticonvulsant activity at

Identification of HIV-1 Integrase Inhibitors Based on a Four-Point Pharmacophore

Abstract: The rapid emergence of human immunodeficiency virus (HIV) strains resistant to available drugs implies that effective treatment modalities will require the use of a combination of drugs targeting different sites of the HIV life cycle. Because the virus cannot replicate without integration into a host chromosome, HIV-1 integrase (IN) is an attractive therapeutic target. Thus, an effective IN inhibitor should provide additional benefit in combination chemotherapy. A four-point pharmacophore has been identified based on the structures of quinalizarin and purpurin, which were found to be potent IN inhibitors using both a preintegration complex assay and a purified enzyme assay in vitro. Searching with this four-point pharmacophore in the 'open' part of the National Cancer Institute three-dimensional structure database produced 234 compounds containing the pharmacophore. Sixty of these compounds were tested for their inhibitory activity against IN using the purified enzyme; 19 were found to be active against IN with IC50 values of less than 100 microM, among which 10 had IC50 values of less than 10 microM. These inhibitors can further serve as leads, and studies are in progress to design novel inhibitors based on the results presented in this study.

Design and synthesis of a series of 6-substituted-2-pyridinylmethylamine derivatives as novel, high-affinity, selective agonists at 5-HT1A receptors

Abstract: A search for novel, selective agonists with high intrinsic activity at the 5-HT1A subtype of serotonin (5-HT) receptors was undertaken. Mechanistic and thermodynamic considerations led to the design of 6-substituted-2-pyridinylmethylamine as a potential 5-HT1A pharmacophore. Various adducts derived from the 6-substituted-2-pyridinylmethylamine moiety were tested for their affinity at 5-HT1A, α1-adrenergic, and D2-dopaminergic receptors. Compounds with high affinity for 5-HT1A receptors (pKi ≥ 8) were examined for agonist properties by measuring their ability to inhibit forskolin-stimulated cAMP production in HA7 cells (i.e., HeLa cells permanently transfected with the h5-HT1A receptor gene and expressing the h5-HT1A receptor protein). Several compounds of the type aryl{4-[(6-substituted-pyridin-2-ylmethylamino)methyl]piperidin-1-yl}methanone had nanomolar affinity for 5-HT1A binding sites and were more than 500-fold selective with respect to α1 and D2 sites. Importantly, their 5-HT1A agonist properties we...

Derivation of a three-dimensional pharmacophore model of substance P antagonists bound to the neurokinin-1 receptor.

Abstract: Constrained systematic search was used in an exhaustive conformational analysis of a structurally diverse set of substance P (SP) antagonists to identify a unique hypothesis for their bound conformation at the neurokinin-1 receptor. In this conformation, two aromatic groups essential for high affinity adopt a perpendicular or edge-on arrangement. This pharmacophore hypothesis for the receptor-bound conformation was used in a comparative molecular field analysis (CoMFA) of an expanded set of SP antagonists, and the predictive ability of the resulting three-dimensional quantitative structure−activity relationship (3D-QSAR) was evaluated against a test set of SP antagonists different from those in the training set. This CoMFA model based on the Constrained Search alignment yielded significant cross-validated, conventional, and predictive r2 values equal to 0.70, 0.93, and 0.82, respectively. For comparison, the SP antagonists were forced into an alternative poorer alignment in which the two aromatic rings we...

Discovery and Preliminary SAR Studies of a Novel, Nonsteroidal Progesterone Receptor Antagonist Pharmacophore

Abstract: A series of 6-aryl-1,2-dihydro-2,2,4-trimethylquinolines was synthesized and tested for functional activity on the human progesterone receptor isoform B (hPR-B) in mammalian (CV-1) cells. The lead compound LG001447 (1,2-dihydro-2,2,4-trimethyl-6-phenylquinoline) was discovered via directed high throughput screening of a defined chemical library utilizing an hPR-B cotransfection assay. Electron-withdrawing substituents at the meta position of the C(6) aryl group afforded substantial improvements in hPR modulatory activity. Several analogues were able to potently block the effects of progesterone in vitro. Two compounds, 10 (LG120753) and 11 (LG120830) with potencies comparable or equal to the steroidal hPR antagonist onapristone (ZK98,299), were demonstrated to act as antiprogestins in vivo after oral administration to rodents. This is the first disclosure of orally active nonsteroidal antiprogestins.

Quasi-Atomistic Receptor Surface Models: A Bridge between 3-D QSAR and Receptor Modeling

Abstract: A “quasi-atomistic receptor model” refers to a three-dimensional receptor surface, populated with atomistic properties (hydrogen bonds, salt bridges, hydrophobic particles, and solvent) mapped onto it. In contrast to other 3D-QSAR approaches, an algorithm developed at our laboratory allows for the adaptation of the receptor-surface defining envelope to the topology of the individual ligand molecules. In addition, it includes H-bond flip-flop particles which can simultaneously act as H-bond donors and H-bond acceptors toward different ligand molecules, binding to the surrogate within a pharmacophore hypothesis. Such particles mimic amino- acid residues able to engage in differently directed H-bonds at the true biological receptor. Ligand−receptor interaction energies are evaluated using a directional force field for hydrogen bonds and salt bridges. On the basis of a series of ligand molecules with individually adapted receptor envelopes, the software Quasar allows a family of receptor models to be generate...