ABSTRACT
Background Aberrant kallikrein activity is observed in a number of inflammatory dermatoses. Up-regulation of kallikrein-5 (KLK5) activity leads to uncontrolled skin desquamation and cleavage of proteinase-activated receptor-2 (PAR2), causing the release of pro-inflammatory cytokines and disruption of epidermal barrier function. This study aimed to identify KLK5-specific small molecule inhibitors which can serve as the foundation of a novel therapeutic for inflammatory skin disorders. Methods Five chemical libraries (13,569 compounds total) were screened against recombinant KLK5 using a fluorogenic enzymatic assay. Secondary validation was performed on the top 22 primary hits. All hits were docked in the KLK5 crystal structure to rationalize their potential interactions with the protein. Results A naturally occurring compound derived from the wood of Caesalpinia sappan (Brazilin) was identified as a novel KLK5 inhibitor (IC50: 20 µM, Ki: 6.4 µM). Docking suggests that the phenolic moiety of Brazilin binds in the S1-pocket of KLK5 and forms a H-bond with S195 side chain. KLK14 was also found to be susceptible to inhibition by Brazilin with a calculated IC50 value of 14.6 µM. Conclusions Natural KLK5 small molecule inhibitors such as Brazilin, are ideal for topical skin disease drug design and remain a promising therapeutic for severe cases of inflammatory skin disorders. Optimized KLK inhibitors may have increased efficacy as therapeutics and warrant further investigation.
Subject(s)
Benzopyrans/therapeutic use , Kallikreins/antagonists & inhibitors , Skin Diseases/drug therapy , Benzopyrans/pharmacology , HumansABSTRACT
The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML). Selective expression of a short (30-kDa) CCAAT-enhancer binding protein-α (C/EBPα) translational isoform, termed p30, represents the most common type of CEBPA mutation in AML. The molecular mechanisms underlying p30-mediated transformation remain incompletely understood. We show that C/EBPα p30, but not the normal p42 isoform, preferentially interacts with Wdr5, a key component of SET/MLL (SET-domain/mixed-lineage leukemia) histone-methyltransferase complexes. Accordingly, p30-bound genomic regions were enriched for MLL-dependent H3K4me3 marks. The p30-dependent increase in self-renewal and inhibition of myeloid differentiation required Wdr5, as downregulation of the latter inhibited proliferation and restored differentiation in p30-dependent AML models. OICR-9429 is a new small-molecule antagonist of the Wdr5-MLL interaction. This compound selectively inhibited proliferation and induced differentiation in p30-expressing human AML cells. Our data reveal the mechanism of p30-dependent transformation and establish the essential p30 cofactor Wdr5 as a therapeutic target in CEBPA-mutant AML.
Subject(s)
Antineoplastic Agents/pharmacology , Biphenyl Compounds/pharmacology , Dihydropyridines/pharmacology , Gene Expression Regulation, Neoplastic , Histone-Lysine N-Methyltransferase/antagonists & inhibitors , Leukemia, Myeloid, Acute/metabolism , Myeloid-Lymphoid Leukemia Protein/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Amino Acid Sequence , Animals , CCAAT-Enhancer-Binding Proteins/genetics , CCAAT-Enhancer-Binding Proteins/metabolism , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Histones/genetics , Histones/metabolism , Humans , Intracellular Signaling Peptides and Proteins , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Mice , Molecular Docking Simulation , Molecular Sequence Data , Molecular Targeted Therapy , Mutation , Myeloid-Lymphoid Leukemia Protein/genetics , Myeloid-Lymphoid Leukemia Protein/metabolism , Protein Binding , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Structure, Tertiary , Signal Transduction , Tumor Cells, CulturedABSTRACT
The universally conserved Kae1/Qri7/YgjD and Sua5/YrdC protein families have been implicated in growth, telomere homeostasis, transcription and the N6-threonylcarbamoylation (t(6)A) of tRNA, an essential modification required for translational fidelity by the ribosome. In bacteria, YgjD orthologues operate in concert with the bacterial-specific proteins YeaZ and YjeE, whereas in archaeal and eukaryotic systems, Kae1 operates as part of a larger macromolecular assembly called KEOPS with Bud32, Cgi121, Gon7 and Pcc1 subunits. Qri7 orthologues function in the mitochondria and may represent the most primitive member of the Kae1/Qri7/YgjD protein family. In accordance with previous findings, we confirm that Qri7 complements Kae1 function and uncover that Qri7 complements the function of all KEOPS subunits in growth, t(6)A biosynthesis and, to a partial degree, telomere maintenance. These observations suggest that Kae1 provides a core essential function that other subunits within KEOPS have evolved to support. Consistent with this inference, Qri7 alone is sufficient for t(6)A biosynthesis with Sua5 in vitro. In addition, the 2.9 Å crystal structure of Qri7 reveals a simple homodimer arrangement that is supplanted by the heterodimerization of YgjD with YeaZ in bacteria and heterodimerization of Kae1 with Pcc1 in KEOPS. The partial complementation of telomere maintenance by Qri7 hints that KEOPS has evolved novel functions in higher organisms.
Subject(s)
Adenosine/analogs & derivatives , DNA-Binding Proteins/metabolism , Mitochondrial Proteins/chemistry , Mitochondrial Proteins/metabolism , RNA, Transfer/metabolism , Saccharomyces cerevisiae Proteins/chemistry , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/enzymology , Adenosine/biosynthesis , Adenosine/metabolism , Dimerization , Metalloendopeptidases/physiology , Mitochondrial Proteins/physiology , Models, Molecular , Protein Subunits/physiology , RNA, Transfer/chemistry , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/growth & development , Saccharomyces cerevisiae Proteins/physiology , Telomere HomeostasisABSTRACT
WDR5 (WD40 repeat protein 5) is an essential component of the human trithorax-like family of SET1 [Su(var)3-9 enhancer-of-zeste trithorax 1] methyltransferase complexes that carry out trimethylation of histone 3 Lys4 (H3K4me3), play key roles in development and are abnormally expressed in many cancers. In the present study, we show that the interaction between WDR5 and peptides from the catalytic domain of MLL (mixed-lineage leukaemia protein) (KMT2) can be antagonized with a small molecule. Structural and biophysical analysis show that this antagonist binds in the WDR5 peptide-binding pocket with a Kd of 450 nM and inhibits the catalytic activity of the MLL core complex in vitro. The degree of inhibition was enhanced at lower protein concentrations consistent with a role for WDR5 in directly stabilizing the MLL multiprotein complex. Our data demonstrate inhibition of an important protein-protein interaction and form the basis for further development of inhibitors of WDR5-dependent enzymes implicated in MLL-rearranged leukaemias or other cancers.
Subject(s)
Histone-Lysine N-Methyltransferase/metabolism , Myeloid-Lymphoid Leukemia Protein/antagonists & inhibitors , Myeloid-Lymphoid Leukemia Protein/metabolism , Catalytic Domain/physiology , Crystallography, X-Ray , Histone-Lysine N-Methyltransferase/antagonists & inhibitors , Humans , Intracellular Signaling Peptides and Proteins , Protein Binding/physiology , Protein Interaction Domains and Motifs/physiologyABSTRACT
Protein methyltransferases (PMTs) are a novel gene family of therapeutic relevance involved in chromatin-mediated signaling and other biological mechanisms. Most PMTs are organized around the structurally conserved SET domain that catalyzes the methylation of a substrate lysine. A few potent chemical inhibitors compete with the protein substrate, and all are anchored in the channel recruiting the methyl-accepting lysine. We propose a novel strategy to design focused chemical libraries targeting the substrate binding site, where a limited number of warheads each occupying the lysine-channel of multiple enzymes would be decorated by different substituents. A variety of sequence and structure-based approaches used to analyze the diversity of the lysine channel of SET domain PMTs support the relevance of this strategy. We show that chemical fragments derived from published inhibitors are valid warheads that can be used in the design of novel focused libraries targeting other PMTs.
Subject(s)
Protein Methyltransferases/metabolism , Amino Acids/analysis , Chromatin/physiology , Crystallography, X-Ray , Drug Design , Hydrogen Bonding , Ion Channels/metabolism , Lysine/metabolism , Models, Molecular , Phylogeny , Protein Binding , Protein Conformation , Protein Structure, Tertiary , Small Molecule Libraries , Substrate SpecificityABSTRACT
Bent but not broken: cyclic oligoprolines are accessed in a reaction that effectively bends rigid oligoproline peptides (see scheme; TBDMS=tert-butyldimethylsilyl). The stitching is accomplished during macrocyclization enabled by aziridine aldehydes and isocyanides. Molecular modeling studies suggest that electrostatic attraction between the termini of the linear peptide is pivotal for macrocyclization. The macrocycles were studied by circular dichroism with a polyproline II structure being observed in larger macrocycles.
Subject(s)
Macrocyclic Compounds/chemistry , Oligopeptides/chemistry , Organosilicon Compounds/chemistry , Peptides/chemistry , Circular Dichroism , CyclizationABSTRACT
The article presents a Web-based platform for collecting and storing toxicological structural alerts from literature and for virtual screening of chemical libraries to flag potentially toxic chemicals and compounds that can cause adverse side effects. An alert is uniquely identified by a SMARTS template, a toxicological endpoint, and a publication where the alert was described. Additionally, the system allows storing complementary information such as name, comments, and mechanism of action, as well as other data. Most importantly, the platform can be easily used for fast virtual screening of large chemical datasets, focused libraries, or newly designed compounds against the toxicological alerts, providing a detailed profile of the chemicals grouped by structural alerts and endpoints. Such a facility can be used for decision making regarding whether a compound should be tested experimentally, validated with available QSAR models, or eliminated from consideration altogether. The alert-based screening can also be helpful for an easier interpretation of more complex QSAR models. The system is publicly accessible and tightly integrated with the Online Chemical Modeling Environment (OCHEM, http://ochem.eu). The system is open and expandable: any registered OCHEM user can introduce new alerts, browse, edit alerts introduced by other users, and virtually screen his/her data sets against all or selected alerts. The user sets being passed through the structural alerts can be used at OCHEM for other typical tasks: exporting in a wide variety of formats, development of QSAR models, additional filtering by other criteria, etc. The database already contains almost 600 structural alerts for such endpoints as mutagenicity, carcinogenicity, skin sensitization, compounds that undergo metabolic activation, and compounds that form reactive metabolites and, thus, can cause adverse reactions. The ToxAlerts platform is accessible on the Web at http://ochem.eu/alerts, and it is constantly growing.
Subject(s)
Databases, Chemical , Drug-Related Side Effects and Adverse Reactions , Internet , Pharmaceutical Preparations/chemistry , Drug Evaluation, Preclinical , Humans , Quantitative Structure-Activity RelationshipABSTRACT
Installation of sites for metabolism in the lead compound PHA-767408 was the key focus of the IKK-2 inhaled program. This paper reports our efforts to identify a novel series of aminopyridinecarboxamide-based IKK-2 inhibitors, which display low nanomolar potency against IKK-2 with long duration of action (DOA), and metabolically labile to phase I and/or phase II metabolizing enzymes with potential capability for multiple routes of clearance. Several compounds have demonstrated their potential usefulness in the treatment of asthma and chronic obstructive pulmonary disease (COPD).
Subject(s)
Aminopyridines/chemical synthesis , Asthma/drug therapy , I-kappa B Kinase/antagonists & inhibitors , Niacinamide/analogs & derivatives , Protein Kinase Inhibitors/chemical synthesis , Pulmonary Disease, Chronic Obstructive/drug therapy , Pyrazoles/chemical synthesis , Administration, Inhalation , Aminopyridines/chemistry , Aminopyridines/pharmacology , Binding, Competitive , Drug Design , HEK293 Cells , Humans , Indazoles/chemistry , Indazoles/metabolism , Indazoles/pharmacology , Isonicotinic Acids/chemistry , Isonicotinic Acids/metabolism , Isonicotinic Acids/pharmacology , Microsomes, Liver/drug effects , Models, Molecular , Molecular Structure , Molecular Targeted Therapy , Niacinamide/chemical synthesis , Niacinamide/chemistry , Niacinamide/metabolism , Niacinamide/pharmacology , Phenethylamines/metabolism , Potassium Channel Blockers/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrazoles/metabolism , Pyrazoles/pharmacology , Structure-Activity Relationship , Sulfonamides/metabolismABSTRACT
NF-kappaB signaling plays a pivotal role in a variety of pathological conditions. Because of its central role in the overall NF-kappaB regulation, IKK-2 is a viable target for drug discovery. In order to enable structure-based design of IKK-2 inhibitors, we carried out a rational generation of IKK-2 mutants based on induced-fit docking of a selective IKK-2 inhibitor, PHA-408, into the homology model of IKK-2. One mutant we have characterized is a catalytically inactive form of IKK-2, D145A IKK-2, wherein the catalytic aspartic acid, D145 was replaced with alanine. Unlike the WT enzyme, D145A IKK-2 is devoid of kinase activity despite its ability to bind ATP with high affinity and is not phosphorylated at the T loop. In addition, this mutant binds a diverse collection of inhibitors with comparable binding affinities to WT IKK-2. Another interesting mutant we have characterized is F26A IKK-2 (F26 is an aromatic residue located at the very tip of the Gly-rich loop). Pre-incubation of F26A IKK-2 with PHA-408 revealed the role of F26 in the time-dependent binding of this inhibitor. Thus, functional characterization of these mutants provides the first evidence showing the role of a Gly-rich loop residue of a kinase in binding kinetics. These two mutants along with others that we have identified could be used to validate homology models and probe the interactions of IKK-2 with a variety of inhibitors.
Subject(s)
I-kappa B Kinase/metabolism , Animals , Cells, Cultured , Computer Simulation , Drug Discovery/methods , Humans , I-kappa B Kinase/biosynthesis , I-kappa B Kinase/chemistry , I-kappa B Kinase/genetics , Indazoles/chemistry , Indazoles/metabolism , Isonicotinic Acids/chemistry , Isonicotinic Acids/metabolism , Kinetics , Models, Molecular , Mutagenesis, Site-Directed , Mutation , Phosphorylation , Protein Binding , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Spodoptera , Structural Homology, ProteinABSTRACT
The work described herein demonstrates the utility of structure-based drug design (SBDD) in shifting the binding mode of an HTS hit from a DFG-in to a DFG-out binding mode resulting in a class of novel potent CSF-1R kinase inhibitors suitable for lead development.
Subject(s)
Protein Kinase Inhibitors/chemistry , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Binding Sites , Crystallography, X-Ray , Drug Design , High-Throughput Screening Assays , Hydrogen Bonding , Molecular Conformation , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Receptor, Macrophage Colony-Stimulating Factor/metabolismABSTRACT
Optimization of kinase selectivity for a set of benzothiophene MK2 inhibitors provided analogs with potencies of less than 500 nM in a cell based assay. The selectivity of the inhibitors can be rationalized by examination of X-ray crystal structures of inhibitors bound to MK2.
Subject(s)
MAP Kinase Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Thiophenes/chemistry , Binding Sites , Cell Line, Tumor , Crystallography, X-Ray , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 2/metabolism , Drug Design , Humans , MAP Kinase Kinase 2/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacologyABSTRACT
Identification of potent benzothiophene inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK2), structure-activity relationship (SAR) studies, selectivity assessments against CDK2, cellular potency and mechanism of action are presented. Crystallographic data provide a rationale for the observed MK2 potency as well as selectivity over CDK2 for this class of inhibitors.
Subject(s)
MAP Kinase Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Thiophenes/chemistry , Binding Sites , Cell Line, Tumor , Crystallography, X-Ray , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 2/metabolism , Humans , MAP Kinase Kinase 2/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/pharmacologyABSTRACT
A large variety of log P calculation methods failed to produce sufficient accuracy in log P prediction for two in-house datasets of more than 96000 compounds contrary to their significantly better performances on public datasets. The minimum Root Mean Squared Error (RMSE) of 1.02 and 0.65 were calculated for the Pfizer and Nycomed datasets, respectively, in the 'out-of-box' implementation. Importantly, the use of local corrections (LC) implemented in the ALOGPS program based on experimental in-house log P data significantly reduced the RMSE to 0.59 and 0.48 for the Pfizer and Nycomed datasets, respectively, instantly without retraining the model. Moreover, more than 60% of molecules predicted with the highest confidence in each set had a mean absolute error (MAE) less than 0.33 log units that is only ca. 10% higher than the estimated variation in experimental log P measurements for the Pfizer dataset. Therefore, following this retrospective analysis, we suggest that the use of the predicted log P values with high confidence may eliminate the need of experimentally testing every other compound. This strategy could reduce the cost of measurements for pharmaceutical companies by a factor of 2, increase the confidence in prediction at the analog design stage of drug discovery programs, and could be extended to other ADMET properties.
Subject(s)
Forecasting/methods , Pharmaceutical Preparations/chemistry , Algorithms , Computer Simulation , Databases, Factual , Lipids/chemistry , Neural Networks, Computer , Reproducibility of Results , Software , SolubilityABSTRACT
A new class of potent kinase inhibitors selective for mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2 or MK-2) for the treatment of rheumatoid arthritis has been prepared and evaluated. These inhibitors have IC50 values as low as 10 nM against the target and have good selectivity profiles against a number of kinases including CDK2, ERK, JNK, and p38. These MK-2 inhibitors have been shown to suppress TNFalpha production in U397 cells and to be efficacious in an acute inflammation model. The structure-activity relationships of this series, the selectivity for MK-2 and their activity in both in vitro and in vivo models are discussed. The observed selectivity is discussed with the aid of an MK-2/inhibitor crystal structure.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyridines/chemical synthesis , Pyrroles/chemical synthesis , Acute Disease , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Crystallography, X-Ray , Humans , Inflammation/drug therapy , Intracellular Signaling Peptides and Proteins , Models, Molecular , Protein Serine-Threonine Kinases/chemistry , Pyridines/chemistry , Pyridines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/biosynthesis , U937 CellsABSTRACT
There have recently been developments in the methods used to access the accuracy of the prediction and applicability domain of absorption, distribution, metabolism, excretion and toxicity models, and also in the methods used to predict the physicochemical properties of compounds in the early stages of drug development. The methods are classified into two main groups: those based on the analysis of similarity of molecules, and those based on the analysis of calculated properties. An analysis of octanol-water distribution coefficients is used to exemplify the consistency of estimated and calculated accuracy of the ALOGPS program (http://www.vcclab.org) to predict in-house and publicly available datasets.
Subject(s)
Drug Design , Pharmaceutical Preparations/chemistry , Algorithms , Animals , Computer Simulation , Drug-Related Side Effects and Adverse Reactions , Humans , Inactivation, Metabolic , Models, Biological , Pharmaceutical Preparations/metabolism , Reproducibility of ResultsABSTRACT
Tissue kallikreins are a family of fifteen secreted serine proteases encoded by the largest protease gene cluster in the human genome. In the past decade, substantial progress has been made in characterizing the natural substrates, endogenous inhibitors and in vivo functions of kallikreins, and studies have delineated important pathophysiological roles for these proteases in a variety of tissues. Thus, kallikreins are now considered attractive targets for the development of novel therapeutics for airway, cardiovascular, tooth, brain, skin and neoplastic diseases. In this Review, we discuss recent advances in our understanding of the physiological functions and pathological implications of kallikrein proteases, and highlight progress in the identification of kallikrein inhibitors, which together are bringing us closer to therapeutically targeting kallikreins in selected disease settings.
Subject(s)
Serine Proteinase Inhibitors/therapeutic use , Tissue Kallikreins/antagonists & inhibitors , Animals , Humans , Models, Molecular , Serine Proteases/genetics , Serine Proteases/physiology , Tissue Kallikreins/genetics , Tissue Kallikreins/physiologyABSTRACT
Evaluation of the ALOGPS, ACD Labs LogD, and PALLAS PrologD suites to calculate the log D distribution coefficient resulted in high root-mean-squared error (RMSE) of 1.0-1.5 log for two in-house Pfizer's log D data sets of 17,861 and 640 compounds. Inaccuracy in log P prediction was the limiting factor for the overall log D estimation by these algorithms. The self-learning feature of the ALOGPS (LIBRARY mode) remarkably improved the accuracy in log D prediction, and an rmse of 0.64-0.65 was calculated for both data sets.
Subject(s)
Biological Availability , Drug Design , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/metabolism , Quantitative Structure-Activity Relationship , Software , 1-Octanol , Administration, Oral , Chemistry, Pharmaceutical , Databases, Factual , Drug Industry , Hydrogen-Ion Concentration , Neural Networks, Computer , Private Sector , Solubility , WaterABSTRACT
Endoplasmic reticulum (ER) stress activates the unfolded protein response and its dysfunction is linked to multiple diseases. The stress transducer IRE1α is a transmembrane kinase endoribonuclease (RNase) that cleaves mRNA substrates to re-establish ER homeostasis. Aromatic ring systems containing hydroxy-aldehyde moieties, termed hydroxy-aryl-aldehydes (HAA), selectively inhibit IRE1α RNase and thus represent a novel chemical series for therapeutic development. We solved crystal structures of murine IRE1α in complex with three HAA inhibitors. HAA inhibitors engage a shallow pocket at the RNase-active site through pi-stacking interactions with His910 and Phe889, an essential Schiff base with Lys907 and a hydrogen bond with Tyr892. Structure-activity studies and mutational analysis of contact residues define the optimal chemical space of inhibitors and validate the inhibitor-binding site. These studies lay the foundation for understanding both the biochemical and cellular functions of IRE1α using small molecule inhibitors and suggest new avenues for inhibitor design.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Membrane Proteins/antagonists & inhibitors , Protein Serine-Threonine Kinases/antagonists & inhibitors , Structure-Activity Relationship , Aldehydes/chemistry , Aldehydes/pharmacology , Benzaldehydes/chemistry , Benzaldehydes/pharmacology , Binding Sites , CD59 Antigens/metabolism , Catalytic Domain , Cell Line, Tumor/drug effects , Coumarins/chemistry , Coumarins/pharmacology , Crystallography, X-Ray , DNA Mutational Analysis , DNA-Binding Proteins/genetics , Enzyme Inhibitors/metabolism , Humans , Membrane Proteins/chemistry , Membrane Proteins/genetics , Membrane Proteins/metabolism , Molecular Structure , Morpholines/chemistry , Morpholines/pharmacology , Plasmacytoma/drug therapy , Plasmacytoma/pathology , Protein Conformation , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Regulatory Factor X Transcription Factors , Ribonucleases/metabolism , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Transcription Factors/geneticsABSTRACT
Molecular field topology analysis, scaffold hopping, and molecular docking were used as complementary computational tools for the design of repellents for Aedes aegypti, the insect vector for yellow fever, chikungunya, and dengue fever. A large number of analogues were evaluated by virtual screening with Glide molecular docking software. This produced several dozen hits that were either synthesized or procured from commercial sources. Analysis of these compounds by a repellent bioassay resulted in a few highly active chemicals (in terms of minimum effective dosage) as viable candidates for further hit-to-lead and lead optimization effort.