Publications by authors named "Taraneh Mirzadegan"

22 Publications

  • Page 1 of 1

Impact of Protein Preparation on Resulting Accuracy of FEP Calculations.

J Chem Inf Model 2020 11 2;60(11):5287-5289. Epub 2020 Aug 2.

Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, California 92121, United States.

Relative free energy perturbation (FEP) methods have become increasingly popular within the pharmaceutical industry; however, despite time constraints within drug discovery cycles, caution should be applied in the deployment of such methods as protein preparation and system setup can greatly impact the accuracy of free energy predictions.
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http://dx.doi.org/10.1021/acs.jcim.0c00445DOI Listing
November 2020

A computational approach yields selective inhibitors of human excitatory amino acid transporter 2 (EAAT2).

J Biol Chem 2020 03 20;295(13):4359-4366. Epub 2020 Feb 20.

Discovery Sciences, Janssen Research and Development, San Diego, California 92121.

Excitatory amino acid transporters (EAATs) represent a protein family that is an emerging drug target with great therapeutic potential for managing central nervous system disorders characterized by dysregulation of glutamatergic neurotransmission. As such, it is of significant interest to discover selective modulators of EAAT2 function. Here, we applied computational methods to identify specific EAAT2 inhibitors. Utilizing a homology model of human EAAT2, we identified a binding pocket at the interface of the transport and trimerization domain. We next conducted a high-throughput virtual screen against this site and identified a selective class of EAAT2 inhibitors that were tested in glutamate uptake and whole-cell electrophysiology assays. These compounds represent potentially useful pharmacological tools suitable for further exploration of the therapeutic potential of EAAT2 and may provide molecular insights into mechanisms of allosteric modulation for glutamate transporters.
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http://dx.doi.org/10.1074/jbc.AC119.011190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105306PMC
March 2020

Breaking the Glass Ceiling in Simulation and Modeling: Women in Pharmaceutical Discovery.

J Med Chem 2020 03 22;63(5):1929-1936. Epub 2020 Jan 22.

Discovery Sciences, Janssen Research and Development, San Diego, California 92121, United States.

The topic of gender equality within the United States workforce is receiving a great deal of attention. The field of chemistry is no exception and is increasingly focused on taking steps to achieve gender diversity within the chemistry workforce. Over the past several years, many computational chemistry groups within large pharmaceutical companies have realized growth in the number of women, and here we discuss the key factors that we believe have played a role in attracting and retaining the authors of this review as computational chemists in pharma. Furthermore, we combine our professional experiences in the context of how computational methodology and technology have evolved over the past decades and how that evolution has facilitated the inclusion of more women into the field. Our hope is to be a part of a solution and provide insight that will allow the chemistry workforce to continue to make steps forward in attaining gender diversity in the workplace.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01512DOI Listing
March 2020

Beyond Traditional Structure-Based Drug Design: The Role of Iron Complexation, Strain, and Water in the Binding of Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylase 2.

ACS Omega 2019 Apr 12;4(4):6703-6708. Epub 2019 Apr 12.

Janssen Research & Development, San Diego, California 92121, United States.

A combination of structure-based drug design and medicinal chemistry efforts led us from benzimidazole-2-carboxamide with modestly active hypoxia-inducible factor prolyl hydroxylase 2 inhibition to certain benzimidazole-2-pyrazole carboxylic acids that were more potent as well as orally efficacious stimulators of erythropoietin secretion in our in vivo mouse model. To better understand the structure-activity relationship, it was necessary to account for (i) the complexation of the ligand with the active site Fe, (ii) the strain incurred by the ligand upon binding, and (iii) certain key water interactions identified by a crystal structure analysis. With this more complete computational model, we arrived at an overarching paradigm that accounted for the potency differences between benzimidazole-2-carboxamide and benzimidazole-2-pyrazole carboxylic acid enzyme inhibitors. Moreover, the computational paradigm allowed us to anticipate that the bioisostere replacement strategy (amide → pyrazole), which had shown success in the benzimidazole series, was not generally applicable to other series. This illustrates that to fully reconcile the important ligand-active site interactions for certain targets, one often needs to move beyond traditional structure-based drug design (such as crystallographic analysis, docking, etc.) and appeal to a higher level of computational theory.
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http://dx.doi.org/10.1021/acsomega.9b00199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547624PMC
April 2019

Accelerating Lead Identification by High Throughput Virtual Screening: Prospective Case Studies from the Pharmaceutical Industry.

J Chem Inf Model 2019 05 13;59(5):2046-2062. Epub 2019 Mar 13.

Discovery Sciences , Janssen Research and Development , Welsh and McKean Roads , Spring House , Pennsylvania 19477 , United States.

At the onset of a drug discovery program, the goal is to identify novel compounds with appropriate chemical features that can be taken forward as lead series. Here, we describe three prospective case studies, Bruton Tyrosine Kinase (BTK), RAR-Related Orphan Receptor γ t (RORγt), and Human Leukocyte Antigen DR isotype (HLA-DR) to illustrate the positive impact of high throughput virtual screening (HTVS) on the successful identification of novel chemical series. Each case represents a project with a varying degree of difficulty due to the amount of structural and ligand information available internally or in the public domain to utilize in the virtual screens. We show that HTVS can be effectively employed to identify a diverse set of potent hits for each protein system even when the gold standard, high resolution structural data or ligand binding data for benchmarking, is not available.
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http://dx.doi.org/10.1021/acs.jcim.8b00941DOI Listing
May 2019

Predicting the Binding of Fatty Acid Amide Hydrolase Inhibitors by Free Energy Perturbation.

J Chem Theory Comput 2018 Nov 23;14(11):5815-5822. Epub 2018 Oct 23.

Janssen Research and Development , 3210 Merryfield Row , San Diego , California 92121 , United States.

Since a goal of most drug discovery projects in either academia or industry is to design molecules that selectively bind to the desired protein, determination of protein-ligand binding free energies is of utmost importance in computer aided drug design. With the help of significant improvements in computer power, enhanced sampling techniques and accuracy of force fields, FEP (free energy perturbation) is becoming an important tool to estimate binding free energies in many drug discovery projects both retrospectively and prospectively. We have evaluated the ability of Schrödinger's FEP+ to predict relative binding free energies of a congeneric series of noncovalent fatty acid amide hydrolase (FAAH) inhibitors using an in-house crystal structure. This study shows that although an impressively accurate correlation can be obtained with experimental ICs considering small perturbations on the deeper side of the pocket, the same was not observed with small perturbations on the relatively more open-ended and solvent-accessible side of the pocket. To understand these observations, we thoroughly investigated several key factors including the sampling of asymmetrically substituted rings, different perturbation maps, impact of simultaneous perturbations at two different ends of the ligand, and selecting the perturbations in a "chemically sensible" way.
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http://dx.doi.org/10.1021/acs.jctc.8b00672DOI Listing
November 2018

An Analysis of Different Components of a High-Throughput Screening Library.

J Chem Inf Model 2018 10 26;58(10):2057-2068. Epub 2018 Sep 26.

Janssen Pharmaceutical Research and Development , 3210 Merryfield Row , La Jolla , California 92121 , United States.

Since many projects at pharmaceutical organizations get their start from a high-throughput screening (HTS) campaign, improving the quality of the HTS deck can improve the likelihood of discovering a high-quality lead molecule that can be progressed to a drug candidate. Over the past decade, Janssen has implemented several strategies for external compound acquisition to augment the screening deck beyond the chemical space and number of molecules synthesized for internal projects. In this report, we analyzed the performance of each of those compound collections in the screening campaigns performed internally within Janssen during the last five years. We classified the screening library into two broad categories: Internal and External. The comparison of the performance of these sets of libraries was done by considering the primary, confirmation, and dose response hit rates. Our analysis revealed that Internal compounds (resulting from numerous medicinal chemistry efforts against diverse protein targets) have higher average confirmation hit rates than External ones; however, actives from both categories show similar probabilities of hitting multiple distinct targets. We also investigated the property landscape of both sets of libraries to identify the key elements which make a difference in these categories of compounds. From this analysis, Janssen aims to understand the descriptor landscape of the compounds with the highest hit rates and to use them for improving its future acquisition strategies as well as to inform our plating strategy.
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http://dx.doi.org/10.1021/acs.jcim.8b00258DOI Listing
October 2018

Determination of a Focused Mini Kinase Panel for Early Identification of Selective Kinase Inhibitors.

J Chem Inf Model 2018 07 22;58(7):1434-1440. Epub 2018 Jun 22.

We analyzed an extensive data set of 3000 Janssen kinase inhibitors (spanning some 40 therapeutic projects) profiled at 414 kinases in the DiscoverX KINOME scan to better understand the necessity of using such a full kinase panel versus simply profiling one's compound at a much smaller number of kinases, or mini kinase panel (MKP), to assess its selectivity. To this end, we generated a series of MKPs over a range of sizes and of varying kinase membership using Monte Carlo simulations. By defining the kinase hit index (KHI), we quantified a compound's selectivity based on the number of kinases it hits. We find that certain combinations (rather than a random selection) of kinases can result in a much lower average error. Indeed, we identified a focused MKP with a 45.1% improvement in the average error (compared to random) that yields an overall correlation of R = 0.786-0.826 for the KHI compared to the full kinase panel value. Unlike using a full kinase panel, which is both time and cost restrictive, a focused MKP is amenable to the triaging of all early stage compounds. In this way, promiscuous compounds are filtered out early on, leaving the most selective compounds for lead optimization.
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http://dx.doi.org/10.1021/acs.jcim.8b00222DOI Listing
July 2018

Dynamic Structural Differences between Human and Mouse STING Lead to Differing Sensitivity to DMXAA.

Biophys J 2018 01;114(1):32-39

Discovery Sciences, Janssen Research and Development, San Diego, California.

The stimulator-of-interferon-genes (STING) protein is involved in innate immunity. It has recently been shown that modulation of STING can lead to an aggressive antitumor response. DMXAA is an antitumor agent that had shown great promise in murine models but failed in human clinical trials. The molecular target of DMXAA was subsequently shown to be murine STING (mSTING); however, human STING (hSTING) is insensitive to DMXAA. Molecular dynamics simulations were employed to investigate the differences between hSTING and mSTING that could influence DMXAA binding. An initial set of simulations was performed to investigate a single lid region mutation G230I in hSTING (corresponding residue in mSTING is an Ile), which rendered the protein sensitive to DMXAA. The simulations found that an Ile side chain was enough to form a steric barrier that prevents exit of DMXAA, whereas in WT hSTING, the Gly residue that lacks a side chain formed a porous lid region that allowed DMXAA to exit. A second set of molecular dynamics simulations compared the tendency of STING to be in an open-inactive conformation or a closed-active conformation. The results show that hSTING prefers to be in an open-inactive conformation even with cGAMP, the native ligand, bound. On the other hand, mSTING prefers a closed-active conformation even without a ligand bound. These results highlight the challenges in translating a mouse active STING compound into a human active compound, while also providing avenues to pursue for designing a small-molecule drug targeting human STING.
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http://dx.doi.org/10.1016/j.bpj.2017.10.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773749PMC
January 2018

Structural Basis of Small-Molecule Aggregate Induced Inhibition of a Protein-Protein Interaction.

J Med Chem 2017 04 16;60(8):3511-3517. Epub 2017 Mar 16.

Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , Spring House, Pennsylvania 19477, United States.

A prevalent observation in high-throughput screening and drug discovery programs is the inhibition of protein function by small-molecule compound aggregation. Here, we present the X-ray structural description of aggregation-based inhibition of a protein-protein interaction involving tumor necrosis factor α (TNFα). An ordered conglomerate of an aggregating small-molecule inhibitor (JNJ525) induces a quaternary structure switch of TNFα that inhibits the protein-protein interaction between TNFα and TNFα receptors. SPD-304 may employ a similar mechanism of inhibition.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01836DOI Listing
April 2017

A Prospective Virtual Screening Study: Enriching Hit Rates and Designing Focus Libraries To Find Inhibitors of PI3Kδ and PI3Kγ.

J Med Chem 2016 05 28;59(9):4302-13. Epub 2016 Apr 28.

Discovery Sciences and ‡Immunology, Janssen Research & Development , San Diego, California 92121, United States.

Here, we report a high-throughput virtual screening (HTVS) study using phosphoinositide 3-kinase (both PI3Kγ and PI3Kδ). Our initial HTVS results of the Janssen corporate database identified small focused libraries with hit rates at 50% inhibition showing a 50-fold increase over those from a HTS (high-throughput screen). Further, applying constraints based on "chemically intuitive" hydrogen bonds and/or positional requirements resulted in a substantial improvement in the hit rates (versus no constraints) and reduced docking time. While we find that docking scoring functions are not capable of providing a reliable relative ranking of a set of compounds, a prioritization of groups of compounds (e.g., low, medium, and high) does emerge, which allows for the chemistry efforts to be quickly focused on the most viable candidates. Thus, this illustrates that it is not always necessary to have a high correlation between a computational score and the experimental data to impact the drug discovery process.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01974DOI Listing
May 2016

Identification of structural motifs critical for epstein-barr virus-induced molecule 2 function and homology modeling of the ligand docking site.

Mol Pharmacol 2012 Dec 28;82(6):1094-103. Epub 2012 Aug 28.

Janssen Pharmaceutical Research and Development, San Diego, California, USA.

Epstein-Barr virus-induced molecule 2 (EBI2) (also known as G-protein-coupled receptor 183) is a G-protein-coupled receptor (GPCR) that is best known for its role in B cell migration and localization. Our recent deorphanization effort led to the discovery of 7α,25-dihydroxycholesterol (7α,25-OHC) as the endogenous ligand for EBI2, which provides a tool for mechanistic studies of EBI2 function. Because EBI2 is the first GPCR known to bind and to be activated by an oxysterol, the goal of this study was to understand the molecular and structural bases for its ligand-dependent activation; this was achieved by identifying structural moieties in EBI2 or in 7α,25-OHC that might affect receptor-ligand interactions. By using a series of chemically related OHC analogs, we demonstrated that all three hydroxyl groups in 7α,25-OHC contributed to ligand-induced activation of the receptor. To determine the location and composition of the ligand binding domain in EBI2, we used a site-directed mutagenesis approach and generated mutant receptors with single amino acid substitutions at selected positions of interest. Biochemical and pharmacological profiling of these mutant receptors allowed for structure-function analyses and revealed critical motifs that likely interact with 7α,25-OHC. By using a hybrid β(2)-adrenergic receptor-C-X-C chemokine receptor type 4 structure as a template, we created a homology model for EBI2 and optimized the docking of 7α,25-OHC into the putative ligand binding site, so that the hydroxyl groups interact with residues Arg87, Asn114, and Glu183. This model of ligand docking yields important structural insight into the molecular mechanisms mediating EBI2 function and may facilitate future efforts to design novel therapeutic agents that target EBI2.
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http://dx.doi.org/10.1124/mol.112.080275DOI Listing
December 2012

3,5-Dihydroxybenzoic acid, a specific agonist for hydroxycarboxylic acid 1, inhibits lipolysis in adipocytes.

J Pharmacol Exp Ther 2012 Jun 20;341(3):794-801. Epub 2012 Mar 20.

Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

Niacin raises high-density lipoprotein and lowers low-density lipoprotein through the activation of the β-hydroxybutyrate receptor hydroxycarboxylic acid 2 (HCA2) (aka GPR109a) but with an unwanted side effect of cutaneous flushing caused by vascular dilation because of the stimulation of HCA2 receptors in Langerhans cells in skin. HCA1 (aka GPR81), predominantly expressed in adipocytes, was recently identified as a receptor for lactate. Activation of HCA1 in adipocytes by lactate results in the inhibition of lipolysis, suggesting that agonists for HCA1 may be useful for the treatment of dyslipidemia. Lactate is a metabolite of glucose, suggesting that HCA1 may also be involved in the regulation of glucose metabolism. The low potency of lactate to activate HCA1, coupled with its fast turnover rate in vivo, render it an inadequate tool for studying the biological role of lactate/HCA1 in vivo. In this article, we demonstrate the identification of 3-hydroxybenzoic acid (3-HBA) as an agonist for both HCA2 and HCA1, whereas 3,5-dihydroxybenzoic acid (3,5-DHBA) is a specific agonist for only HCA1 (EC(50) ∼150 μM). 3,5-DHBA inhibits lipolysis in wild-type mouse adipocytes but not in HCA1-deficient adipocytes. Therefore, 3,5-DHBA is a useful tool for the in vivo study of HCA1 function and offers a base for further HCA1 agonist design. Because 3-HBA and 3,5-DHBA are polyphenolic acids found in many natural products, such as fruits, berries, and coffee, it is intriguing to speculate that other heretofore undiscovered natural substances may have therapeutic benefits.
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http://dx.doi.org/10.1124/jpet.112.192799DOI Listing
June 2012

Library enhancement through the wisdom of crowds.

J Chem Inf Model 2011 Dec 14;51(12):3275-86. Epub 2011 Nov 14.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

We present a novel approach for enhancing the diversity of a chemical library rooted on the theory of the wisdom of crowds. Our approach was motivated by a desire to tap into the collective experience of our global medicinal chemistry community and involved four basic steps: (1) Candidate compounds for acquisition were screened using various structural and property filters in order to eliminate clearly nondrug-like matter. (2) The remaining compounds were clustered together with our in-house collection using a novel fingerprint-based clustering algorithm that emphasizes common substructures and works with millions of molecules. (3) Clusters populated exclusively by external compounds were identified as "diversity holes," and representative members of these clusters were presented to our global medicinal chemistry community, who were asked to specify which ones they liked, disliked, or were indifferent to using a simple point-and-click interface. (4) The resulting votes were used to rank the clusters from most to least desirable, and to prioritize which ones should be targeted for acquisition. Analysis of the voting results reveals interesting voter behaviors and distinct preferences for certain molecular property ranges that are fully consistent with lead-like profiles established through systematic analysis of large historical databases.
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http://dx.doi.org/10.1021/ci200446yDOI Listing
December 2011

Study of GPR81, the lactate receptor, from distant species identifies residues and motifs critical for GPR81 functions.

Mol Pharmacol 2011 Nov 23;80(5):848-58. Epub 2011 Aug 23.

Johnson and Johnson Pharmaceutical Research and Development, San Diego, CA 92121, USA.

Receptors from distant species may have conserved functions despite significant differences in protein sequences. Whereas the noncritical residues are often changed in distant species, the amino acids critical in receptor functions are often conserved. Studying the conserved residues between receptors from distant species offers valuable information to probe the roles of residues in receptor function. We identified two zebrafish receptors (zGPR81-1 and zGPR81-2) that show approximately 60% identity to human GPR81, GPR109a, and GPR109b but respond only to l-lactate and not to the GPR109a ligands. Protein sequence comparison among zebrafish GPR81s, mammalian GPR81s, GPR109a, and GPR109b identified a common structure (six Cys residues at the extracellular domains that potentially form three disulfide bonds) in this subfamily of receptors. In addition, a number of residues conserved in all GPR81s but not in GPR109s have been identified. Furthermore, we identified a conserved motif, C165-E166-S167-F168, at the second extracellular loop of GPR81. Using site-directed mutagenesis, we showed that Arg71 at the transmembrane domain 2 is very critical for GPR81 function. In addition, we demonstrated that the C165-E166-S167-F168 motif at the second extracellular loop is critical for GPR81 function, and the conserved six Cys residues at the extracellular regions are necessary for GPR81 function. It is important to mention that for those residues important for GPR81 function, the corresponding residues or motifs in GPR109a are also critical for GPR109a function. These findings help us better understand the interaction between lactate and GPR81 and provide useful information for GPR81 ligand design.
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http://dx.doi.org/10.1124/mol.111.074500DOI Listing
November 2011

Chimeric, mutant orexin receptors show key interactions between orexin receptors, peptides and antagonists.

Eur J Pharmacol 2011 Sep 12;667(1-3):120-8. Epub 2011 Jun 12.

Neuroscience Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

Orexin receptor antagonists are being investigated as therapeutic agents for insomnia and addictive disorders. In this study the interactions between the orexin receptors (orexin 1 receptor and orexin 2 receptor), orexin peptides, and small molecule orexin antagonists were explored. To study these phenomena, a variety of mutant orexin receptors was made and tested using receptor binding and functional assays. Domains of the two orexin receptors were exchanged to show the critical ligand binding domains for orexin peptides and representative selective orexin receptor antagonists. Results from domain exchanges between the orexin receptors suggest that transmembrane domain 3 is crucially important for receptor interactions with small molecule antagonists. These data also suggest that the orexin peptides occupy a larger footprint, interacting with transmembrane domain 1, the amino terminus and transmembrane domain 5 as well as transmembrane domain 3. Transmembrane domain 3 has been shown to be an important part of the small molecule binding pocket common to rhodopsin and β2-adrenergic receptors. Additional orexin receptor 2 point mutations were made based on the common arrangement of receptor transmembrane domains shown in the G-protein coupled receptor crystal structure literature and the impact of orexin 2 receptor residue threonine 135 on the ligand selectivity of the 2 orexin receptors. These data support a model of the orexin receptor binding pocket in which transmembrane domains 3 and 5 are prominent contributors to ligand binding and functional activity. The data also illustrate key contact points for ligand interactions in the consensus small molecule pocket of these receptors.
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http://dx.doi.org/10.1016/j.ejphar.2011.05.074DOI Listing
September 2011

Exploration of piperidine-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-Phenyl derivatives with broad potency against resistant mutant viruses.

Bioorg Med Chem Lett 2010 Oct 19;20(20):6020-3. Epub 2010 Aug 19.

Roche R&D Center China, Shanghai, China.

Further investigation of the recently reported piperidine-4-yl-aminopyrimidine class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has been carried out. Thus, preparation of a series of N-phenyl piperidine analogs resulted in the identification of 3-carboxamides as a particularly active series. Analogs such as 28 and 40 are very potent versus wild-type HIV-1 and a broad range of NNRTI-resistant mutant viruses. Synthesis, structure-activity relationship (SAR), clearance data, and crystallographic evidence for the binding motif are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2010.08.068DOI Listing
October 2010

Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-benzyl derivatives with broad potency against resistant mutant viruses.

Bioorg Med Chem Lett 2010 Jul 16;20(14):4215-8. Epub 2010 May 16.

Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.

An analysis of the binding motifs of known HIV-1 non-nucleoside reverse transcriptase inhibitors has led to discovery of novel piperidine-linked aminopyrimidine derivatives with broad activity against wild-type as well as drug-resistant mutant viruses. Notably, the series retains potency against the K103N/Y181C and Y188L mutants, among others. Thus, the N-benzyl compound 5k has a particularly attractive profile. Synthesis and SAR are presented and discussed, as well as crystal structures relating to the binding motifs.
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http://dx.doi.org/10.1016/j.bmcl.2010.05.040DOI Listing
July 2010

Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81.

J Biol Chem 2009 Jan 1;284(5):2811-2822. Epub 2008 Dec 1.

Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121.

Lactic acid is a well known metabolic by-product of intense exercise, particularly under anaerobic conditions. Lactate is also a key source of energy and an important metabolic substrate, and it has also been hypothesized to be a signaling molecule directing metabolic activity. Here we show that GPR81, an orphan G-protein-coupled receptor highly expressed in fat, is in fact a sensor for lactate. Lactate activates GPR81 in its physiological concentration range of 1-20 mM and suppresses lipolysis in mouse, rat, and human adipocytes as well as in differentiated 3T3-L1 cells. Adipocytes from GPR81-deficient mice lack an antilipolytic response to lactate but are responsive to other antilipolytic agents. Lactate specifically induces internalization of GPR81 after receptor activation. Site-directed mutagenesis of GPR81 coupled with homology modeling demonstrates that classically conserved key residues in the transmembrane binding domains are responsible for interacting with lactate. Our results indicate that lactate suppresses lipolysis in adipose tissue through a direct activation of GPR81. GPR81 may thus be an attractive target for the treatment of dyslipidemia and other metabolic disorders.
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http://dx.doi.org/10.1074/jbc.M806409200DOI Listing
January 2009

Design of annulated pyrazoles as inhibitors of HIV-1 reverse transcriptase.

J Med Chem 2008 Dec;51(23):7449-58

Department of Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, California 94304, USA.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of HIV. These regimens are extremely effective in suppressing virus replication. Structure-based optimization of diaryl ether inhibitors led to the discovery of a new series of pyrazolo[3,4-c]pyridazine NNRTIs that bind the reverse transcriptase enzyme of human immunodeficiency virus-1 (HIV-RT) in an expanded volume relative to most other inhibitors in this class.The binding mode maintains the beta13 and beta14 strands bearing Pro236 in a position similar to that in the unliganded reverse transcriptase structure, and the distribution of interactions creates the opportunity for substantial resilience to single point mutations. Several pyrazolopyridazine NNRTIs were found to be highly effective against wild-type and NNRTI-resistant viral strains in cell culture.
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http://dx.doi.org/10.1021/jm800527xDOI Listing
December 2008

Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase.

Bioorg Med Chem Lett 2008 Aug 28;18(15):4352-4. Epub 2008 Jun 28.

Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.

A series of benzyl pyridazinones were evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Several members of this series showed good activity against the wild-type virus and NNRTI-resistant viruses. The binding of inhibitor 5a to HIV-RT was analyzed by surface plasmon resonance spectroscopy. Pharmacokinetic studies of 5a in rat and dog demonstrated that this compound has good oral bioavailability in animal species. The crystal structure of a complex between HIV-RT and inhibitor 4c is also described.
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http://dx.doi.org/10.1016/j.bmcl.2008.06.072DOI Listing
August 2008

Possible role of the 11-cis-retinyl conformation in controlling the dual decay processes of excited rhodopsin.

Proc Natl Acad Sci U S A 2005 Aug 25;102(31):10783-7. Epub 2005 Jul 25.

Department of Chemistry, University of Hawaii, 2545 The Mall, Honolulu, HI 96822, USA.

In this work, we examine how the reported dual decay processes of rhodopsin and binding site stereospecificity can be accounted for by the recently available crystal structure of rhodopsin. Arguments are presented for possible presence of two rhodopsin "rotamers" that fit within the binding cavity. Directed pathways of decay could account for the observed excited decay processes. We summarize evidence for the possible existence of two different ground-state configurations that give rise to two different excited species.
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http://dx.doi.org/10.1073/pnas.0501665102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1182415PMC
August 2005
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