Pharmacophore Search Research Articles

Integration of human immunodeficiency virus as a target for antiretroviral therapy

Most of the studies investigating inhibition of human immunodeficiency virus integration have focused on blocking the enzymatic functions of HIV integrase, with the predominant judgment that integration inhibitors need to block at least one of the integrase-catalyzed reactions. Recent studies, however, have highlighted the importance of other proteins and their contacts with integrase in the preintegration complex, and their involvement in chromosomal integration of the viral DNA. Promising results of clinical trials for two new integrase inhibitors were announced recently, providing the proof of the concept for using HIV-1 integrase inhibitors as antiretroviral therapy. Two strategies are currently employed for the development of novel inhibitors of HIV integrase: synthesis of hybrid molecules comprising core structures of two or more known inhibitors, and three-dimensional pharmacophore searches based on previously discovered compounds. By highlighting the role of the cellular cofactor LEDGF/p75 in HIV integration, novel approaches are indicated that aim to develop compounds altering contact between HIV integrase and integration cofactors. By the discovery of novel inhibitors and targets for HIV integration, coupled with recent studies in characterizing preintegration complex formation, new insight is provided for the rational design of anti-HIV integration inhibitors.

Unsupervised 3D Ring Template Searching as an Ideas Generator for Scaffold Hopping: Use of the LAMDA, RigFit, and Field-Based Similarity Search (FBSS) Methods

Crystal structures taken from the Cambridge Structural Database were used to build a ring scaffold database containing 19 050 3D structures, with each such scaffold then being used to generate a centroid connecting path (CCP) representation. The CCP is a novel object that connects ring centroids, ring linker atoms, and other important points on the connection path between ring centroids. Unsupervised searching in the scaffold and CCP data sets was carried out using the atom-based LAMDA and RigFit search methods and the field-based similarity search method. The performance of these methods was tested with three different ring scaffold queries. These searches demonstrated that unsupervised 3D scaffold searching methods can find not only the types of ring systems that might be retrieved in carefully defined pharmacophore searches (supervised approach) but also additional, structurally diverse ring systems that could form the starting point for lead discovery programs or other scaffold-hopping applications. Not only are the methods effective but some are sufficiently rapid to permit scaffold searching in large chemical databases on a routine basis.

Anti-SARS drug screening by molecular docking.

Summary.Starting from a collection of 1386 druggable compounds obtained from the 3D pharmacophore search, we performed a similarity search to narrow down the scope of docking studies. The template molecule is KZ7088 (Chou et al., 2003, Biochem Biophys Res Commun 308: 148–151). The MDL MACCS keys were used to fingerprint the molecules. The Tanimoto coefficient is taken as the metric to compare fingerprints. If the similarity threshold was 0.8, a set of 50 unique hits and 103 conformers were retrieved as a result of similarity search. The AutoDock 3.011 was used to carry out molecular docking of 50 ligands to their macromolecular protein receptors. Three compounds, i.e., C28H34O4N7Cl, C21H36O5N6, and C21H36O5N6, were found that may be promising candidates for further investigation. The main feature shared by these three potential inhibitors as well as the information of the involved side chains of SARS Cov Mpro may provide useful insights for the development of potent inhibitors against SARS enzyme.

Structure–activity relationships of a series of tariquidar analogs as multidrug resistance modulators

Tariquidar (XR9576) analogs, modulators of cancer multidrug resistance (MDR), were subjected to QSAR and 3D-QSAR analyses. The structural features contributing to anti-MDR activity were identified by the Free-Wilson analysis and pharmacophore search using Hoechst 33342 as a template. 3D-QSAR CoMFA and CoMSIA models were derived and tested. The best models yielded an external predictivity of 0.66–0.75 squared correlation coefficient and outlined HB-acceptor, steric, and hydrophobic fields as the most important 3D properties. On the basis of the QSAR and 3D-QSAR analyses it was suggested that the strong inhibitory potency of the compounds studied is related to the presence of a bulky aromatic ring system with a 3rd positioned heteroatom toward the anthranilamide nucleus in the opposite end of the tetrahydroquinoline group. The results can help in directing the rational design of new generations of potent P-glycoprotein MDR modulators.

Structure-Based Virtual Screening for Low Molecular Weight Chemical Starting Points for Dipeptidyl Peptidase IV Inhibitors

Structure-based virtual screening was performed against the target dipeptidyl peptidase IV (DPP-IV) to identify good chemical starting points for medicinal chemistry. A database of available compounds was filtered by calculated physical properties and undesired chemistry. This database was matched against two in-house designed DPP-IV pharmacophores, and the hits from these pharmacophore searches were docked into a DPP-IV crystal structure. Compounds were then selected for testing and 51 active compounds were identified from a list of 4000 compounds tested. These had activities ranging from 30% to 82% when tested at a concentration of 30 microM in an enzyme inhibition assay.

CO: A chemical ontology for identification of functional groups and semantic comparison of small molecules

A novel chemical ontology based on chemical functional groups automatically, objectively assigned by a computer program, was developed to categorize small molecules. It has been applied to PubChem and the small molecule interaction database to demonstrate its utility as a basic pharmacophore search system. Molecules can be compared using a semantic similarity score based on functional group assignments rather than 3D shape, which succeeds in identifying small molecules known to bind a common binding site. This ontology will serve as a powerful tool for searching chemical databases and identifying key functional groups responsible for biological activities.

The Discovery of Kv1.5 Blockers as a Case Study for the Application of Virtual Screening Approaches.

Different virtual screening techniques are available as alternatives to high throughput screening. These different techniques have been rarely used together on the same target. We had the opportunity to do so in order to discover novel blockers of the voltage-dependent potassium channel Kv1.5, a potential target for the treatment of atrial fibrillation. Our corporate database was searched, using a protein-based pharmacophore, derived from a homology model, as query. As a result, 244 molecules were screened in vitro, 19 of them (7.8%) were found to be active. Five of them, belonging to five different chemical classes, exhibited IC50 values under 10 μM. The performance of this structure-based virtual screening protocol has been compared with those of similarity and ligand-based pharmacophore searches. The analysis of the results supports the conventional wisdom of using as many virtual screening techniques as possible in order to maximize the chance of finding as many chemotypes as possible.

Frontal Affinity Chromatography with MS Detection of EphB2 Tyrosine Kinase Receptor. 2. Identification of Small-Molecule Inhibitors via Coupling with Virtual Screening

We have integrated two complementary methods, high-throughput virtual screening with a "high-content" wet screening technique based on frontal affinity chromatography with mass spectrometry detection (FAC-MS), for identification of hits against the erythropoietin-producing hepatocellular B2 (EphB2) receptor tyrosine kinase domain. Both an EphB2-directed virtual screen combining docking and scoring and a kinase-directed pharmacophore search strategy were used to identify a compound set enriched in bioactive compounds against EphB2. The coupling of virtual screening methodologies with FAC-MS is a unique hybrid approach that can be used to increase the efficacy of both hit discovery and optimization efforts in drug discovery and has successfully identified hits, in particular 19a (36% shift, IC(50) = 5.2 microM, K(d) = 3.3 microM), as inhibitors for EphB2, a potential cancer target.

The Discovery of Kv1.5 Blockers as a Case Study for the Application of Virtual Screening Approaches

Different virtual screening techniques are available as alternatives to high throughput screening. These different techniques have been rarely used together on the same target. We had the opportunity to do so in order to discover novel blockers of the voltage-dependent potassium channel Kv1.5, a potential target for the treatment of atrial fibrillation. Our corporate database was searched, using a protein-based pharmacophore, derived from a homology model, as query. As a result, 244 molecules were screened in vitro, 19 of them (7.8%) were found to be active. Five of them, belonging to five different chemical classes, exhibited IC50 values under 10 microM. The performance of this structure-based virtual screening protocol has been compared with those of similarity and ligand-based pharmacophore searches. The analysis of the results supports the conventional wisdom of using as many virtual screening techniques as possible in order to maximize the chance of finding as many chemotypes as possible.

Combining Pharmacophore Search, Automated Docking, and Molecular Dynamics Simulations as a Novel Strategy for Flexible Docking. Proof of Concept: Docking of Arginine−Glycine−Aspartic Acid-like Compounds into the αvβ3 Binding Site

A novel and highly efficient flexible docking approach is presented where the conformations (internal degrees of freedom) and orientations (external degrees of freedom) of the ligands are successively considered. This hybrid method takes advantage of the synergistic effects of structure-based and ligand-based drug design techniques. Preliminary antagonist-derived pharmacophore determination provides the postulated bioactive conformation. Subsequent docking of this pharmacophore to the receptor crystal structure results in a postulated pharmacophore/receptor binding mode. Pharmacophore-oriented docking of antagonists is subsequently achieved by matching ligand interacting groups with pharmacophore points. Molecular dynamics in water refines the proposed complexes. To validate the method, arginine-glycine-aspartic acid (RGD) containing peptides, pseudopeptides, and RGD-like antagonists were docked to the crystal structure of alphavbeta3 holoprotein and apoprotein. The proposed directed docking was found to be more accurate, faster, and less biased with respect to the protein structure (holo and apoprotein) than DOCK, Autodock, and FlexX docking methods. The successful docking of an antagonist recently cocrystallized with the receptor to both apo and holoprotein is particularly appealing. The results summarized in this report illustrated the efficiency of our light CoMFA/rigid body docking hybrid method.

Virtual screening for SARS-CoV protease based on KZ7088 pharmacophore points.

Pharmacophore modeling can provide valuable insight into ligand-receptor interactions. It can also be used in 3D (dimensional) database searching for potentially finding biologically active compounds and providing new research ideas and directions for drug-discovery projects. To stimulate the structure-based drug design against SARS (severe acute respiratory syndrome), a pharmacophore search was conducted over 3.6 millions of compounds based on the atomic coordinates of the complex obtained by docking KZ7088 (a derivative of AG7088) to SARS CoV M(pro) (coronavirus main proteinase), as reportedly recently (Chou, K. C.; Wei, D. Q.; Zhong, W. Z. Biochem. Biophys. Res. Commun. 2003, 308, 148-151). It has been found that, of the 3.6 millions of compounds screened, 0.07% are with the score satisfying five of the six pharmacophore points. Moreover, each of the hit compounds has been evaluated for druggability according to 13 metrics based on physical, chemical, and structural properties. Of the 0.07% compounds thus retrieved, 17% have a perfect score of 1.0; while 23% with one druggable rule violation, 13% two violations, and 47% more than two violations. If the criterion for druggability is set at a maximum allowance of two rule violations, we obtain that only about 0.03% of the compounds screened are worthy of further tests by experiments. These findings will significantly narrow down the search scope for potential compounds, saving substantial time and money. Finally, the featured templates derived from the current study will also be very useful for guiding the design and synthesis of effective drugs for SARS therapy.

Identification and Mapping of Small‐Molecule Binding Sites in Proteins: Computational Tools for Structure‐Based Drug Design.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Discovery of Substituted 3,4‐Diphenyl‐thiazoles as a Novel Class of Monoamine Transporter Inhibitors Through 3‐D Pharmacophore Search Using a New Pharmacophore Model Derived from Mazindol.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Use of catalyst pharmacophore models for screening of large combinatorial libraries.

Using a data set comprised of literature compounds and structure-activity data for cyclin dependent kinase 2, several pharmacophore hypotheses were generated using Catalyst and evaluated using several criteria. The two best were used in retrospective searches of 10 three-dimensional databases containing over 1,000,000 proprietary compounds. The results were then analyzed for the efficiency with which the hypotheses performed in the areas of compound prioritization, library prioritization, and library design. First as a test of their compound prioritization capabilities, the pharmacophore models were used to search combinatorial libraries that were known to contain CDK active compounds to see if the pharmacophore models could selectively choose the active compounds over the inactive compounds. Second as a test of their utility in library design again the pharmacophore models were used to search the active combinatorial libraries to see if the key synthons were over represented in the hits from the pharmacophore searches. Finally as a test of their ability to prioritize combinatorial libraries, several inactive libraries were searched in addition to the active libraries in order to see if the active libraries produced significantly more hits than the inactive libraries. For this study the pharmacophore models showed potential in all three areas. For compound prioritization, one of the models selected active compounds at a rate nearly 11 times that of random compound selection though in other cases models missed the active compounds entirely. For library design, most of the key fragments were over represented in the hits from at least one of the searches though again some key fragments were missed. Finally, for library prioritization, the two active libraries both produced a significant number of hits with both pharmacophore models, whereas none of the eight inactive libraries produced a significant number of hits for both models.

Discovery of substituted 3,4-Diphenyl-thiazoles as a novel class of monoamine transporter inhibitors through 3-D pharmacophore search using a new pharmacophore model derived from mazindol

Substituted 3,4-diphenyl-1,3-thiazols were identified as a class of novel and potent monoamine transporter inhibitors through a 3-D pharmacophore search using a new pharmacophore model derived from mazindol. The most potent compound ( 13) has K i values of 24 and 23 nM in binding to dopamine transporter and inhibition of dopamine reuptake, respectively.

A web-based 3D-database pharmacophore searching tool for drug discovery.

Three-Dimensional (3D) structural database pharmacophore searching has become a very effective approach for discovery of novel lead compounds in drug discovery. Although several commercial programs are available, these commercial programs are primarily used as a stand alone and require a local database. In recent years, the Internet has become the main medium of choice for multiuser application program distribution. Herein, we describe our development of a Web-based 3D-database pharmacophore-searching tool based on the server-client Web architecture. Both rigid and conformationally flexible searching methods are implemented. Our results show that for a typical three-center rigid pharmacophore search, the run time for searching 50 000 compounds is less than three minutes, and for four-center pharmacophore searching, the run time is less than 10 minutes on a desktop computer. For a flexible 3D-pharmacophore search, the run time for searching 50 000 compounds generally takes between one and several hours. The search results are comparable to those obtained using a commercial program. We expect that this Web-based tool will be very useful for scientists who are interested in 3D-database pharmacophore searching via the Internet.

Discovery of a Novel Dopamine Transporter Inhibitor, 4-Hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-Methylphenyl Ketone, as a Potential Cocaine Antagonist through 3D-Database Pharmacophore Searching. Molecular Modeling, Structure−Activity Relationships, and Behavioral Pharmacological Studies

A novel, fairly potent dopamine transporter (DAT) inhibitor, 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone (3, K(i) values of 492 and 360 nM in binding affinity and inhibition of dopamine reuptake, respectively), with significant functional antagonism against cocaine and a different in vitro pharmacological profile from cocaine at the three transporter sites (dopamine, serotonin, and norepinephrine) was discovered through 3D-database pharmacophore searching. Through structure-activity relationships and molecular modeling studies, we found that hydrophobicity and conformational preference are two additional important parameters that determine affinity at the DAT site. Chemical modifications of the lead compound (3) led to a high affinity analogue (6, K(i) values of 11 and 55 nM in binding affinity and inhibition of dopamine reuptake, respectively). In behavioral pharmacological testing, 6 mimics partially the effect of cocaine in increasing locomotor activity in mice but lacks cocaine-like discriminative stimulus effect in rats. Taken together, these data suggest that 6 represents a promising lead for further evaluations as potential therapy for the treatment of cocaine abuse.

“Scaffold-Hopping” by Topological Pharmacophore Search: A Contribution to Virtual Screening

“Scaffold-Hopping” by Topological Pharmacophore Search: A Contribution to Virtual Screening

“Scaffold-Hopping” by Topological Pharmacophore Search: A Contribution to Virtual Screening

A chemically advanced template search (CATS) based on topological pharmacophore models has been developed as a technique for virtual screening. This technique has successfully identified novel potent Ca(2+) antagonists (such as 2) that have a similar activity to 1 (a known T-channel blocking agent) in a library of several hundred thousand compounds on the basis of a correlation vector representation.

Structure-based Discovery of a Pore-binding Ligand: Towards Assembly Inhibitors for Cholera and Related AB 5Toxins

Cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT) are two closely related multi-subunit AB 5proteins responsible for significant morbidity and mortality worldwide. An attractive strategy to prevent disease by these organisms is to interfere with the assembly process of these toxins, since prevention of toxin formation is better than preventing the effects of a toxin which is already formed. The B subunits form a ring with a central pore which surrounds the C-terminal residues of the A subunit. Low molecular mass compounds which would bind in the pore are likely to inhibit proper assembly of the AB 5toxins. In a pharmacophore search based on two side-chains of the A subunit, 3-methylthio-1,4-diphenyl-1H-1,3,4-triazolium (MDT) was identified as a candidate ligand which might “plug” the pore. A 2.0 Å co-crystal structure revealed that a triplet of MDTs indeed bound to the targeted region in two independent LT B pentamers in a remarkably similar manner. Clearly, MDT is a lead for developing assembly antagonists of CT and LT.