A5085943341- Chemical Synthesis and Analysis
- HIV/AIDS drug development and treatment
- Biochemical and Molecular Research
- Complement system in diseases
- Click Chemistry and Applications
- HIV Research and Treatment
- Protein Degradation and Inhibitors
- Peptidase Inhibition and Analysis
- Protein Structure and Dynamics
- Adenosine and Purinergic Signaling
- Retinal Diseases and Treatments
- Synthesis and biological activity
- Protein Kinase Regulation and GTPase Signaling
- Crystallization and Solubility Studies
- Renal Diseases and Glomerulopathies
- Enzyme Structure and Function
- X-ray Diffraction in Crystallography
- RNA and protein synthesis mechanisms
- Histone Deacetylase Inhibitors Research
- Computational Drug Discovery Methods
- Ubiquitin and proteasome pathways
- Chronic Lymphocytic Leukemia Research
- Receptor Mechanisms and Signaling
- HIV/AIDS Research and Interventions
- PI3K/AKT/mTOR signaling in cancer
Novartis (United States)
2016-2023
Novartis (Switzerland)
2008-2019
Novartis Institutes for BioMedical Research
2008-2019
Frederick National Laboratory for Cancer Research
2004-2008
National Institutes of Health
2003-2008
National Cancer Institute
2002-2008
Science Applications International Corporation (United States)
2005-2007
Center for Cancer Research
2002-2007
United States Department of Health and Human Services
2007
University of Mumbai
2001-2003
SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2), also known as Brahma homologue (BRM), is a Snf2-family DNA-dependent ATPase. BRM and its close Brahma-related gene 1 (BRG1), SMARCA4, are mutually exclusive ATPases the large ATP-dependent SWI/SNF chromatin-remodeling complexes involved in transcriptional regulation expression. No small molecules have been reported that modulate activity via inhibition ATPase activity, an important goal...
Dysregulation of the alternative complement pathway (AP) predisposes individuals to a number diseases including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and C3 glomerulopathy. Moreover, glomerular Ig deposits can lead complement-driven nephropathies. Here we describe discovery highly potent, reversible, selective small-molecule inhibitor factor B, serine protease that drives central amplification loop AP. Oral administration prevents KRN-induced arthritis in...
Abstract The first examples of biologically active monocyclic 1,2‐azaborines have been synthesized and demonstrated to exhibit not only improved in vitro aqueous solubility comparison with their corresponding carbonaceous analogues, but the context a CDK2 inhibitor, also biological activity better vivo oral bioavailability. This proof‐of‐concept study establishes viability as novel pharmacophore distinct pharmacological profiles that can help address challenges associated drug development research.
The β-diketo acids (DKAs) represent a major advance for anti–HIV-1 integrase drug development. We compared the inhibition of HIV-1 by six DKA derivatives using wild-type enzyme or double-mutant F185K/C280S, which has been previously used crystal structure determinations. With enzyme, we found that DKAs could be classified into two groups: those similarly potent in presence magnesium and manganese relatively ineffective magnesium. Both aromatic carboxylic tetrazole functions determined their...
We present here a greatly updated version of an earlier study on the conformational energies protein-ligand complexes in Protein Data Bank (PDB) [Nicklaus et al. Bioorg. Med. Chem. 1995, 3, 411-428], with goal improving all possible aspects such as number and selection ligand instances, energy calculations performed, additional analyses conducted. Starting from about 357,000 instances deposited 2008 Ligand Expo database experimental 3D coordinates small-molecule PDB, we created...
Abstract Sacubitril is an ethyl ester prodrug of LBQ657, the active neprilysin (NEP) inhibitor and a component LCZ696 (sacubitril/valsartan). We report herein three-dimensional structure LBQ657 in complex with human NEP at 2 Å resolution. The crystal unravels binding mode compound occupying S1, S1’ S2’ sub-pockets site, consistent competitive inhibition mode. An induced fit conformational change upon P1’-biphenyl moiety suggests explanation for its selectivity against structurally homologous...
The alternative pathway (AP) of the complement system is a key contributor to pathogenesis several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. serine protease factor B (FB) node in AP integral formation C3 C5 convertase. Despite prominent role FB AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we...
Human immunodeficiency virus type 1 integrase (HIV-1 IN) is an essential enzyme for effective viral replication. Therefore, IN inhibitors are being sought chemotherapy against AIDS. We had previously identified a series of salicylhydrazides as potent in vitro (Neamati, N.; et al. J. Med. Chem. 1998, 41, 3202−3209.). Herein, we report the design, synthesis, and antiviral activity three novel mercaptosalicylhydrazide (MSH) derivatives. MSHs were catalytic core domain inhibited binding to HIV...
Recent clinical evaluation of everolimus for seizure reduction in patients with tuberous sclerosis complex (TSC), a disease overactivated mechanistic target rapamycin (mTOR) signaling, has demonstrated the therapeutic value mTOR inhibitors central nervous system (CNS) indications. Given that is an incomplete inhibitor function, we sought to develop new improved properties and suitable CNS disorders. Starting from in-house purine-based compound, optimization physicochemical thiazolopyrimidine...
The conformations of three 2',3'-difluoro uridine nucleosides were studied by X-ray crystallography, NMR spectroscopy, and ab initio calculations in an attempt to define the roles that two vicinal fluorine atoms play puckering preferences furanose ring. Two compounds examined contained either arabino or xylo dispositions at C2' C3' a 2',3'-dideoxyuridine system. third compound also incorporated configuration on ring but was substituted with 6-azauracil base place uracil. A battery...
Atypical hemolytic uremic syndrome (aHUS) is a rare, progressive, and life-threatening form of thrombotic microangiopathy (TMA) which caused by dysregulation the alternative complement pathway (AP). Complement inhibition an effective therapeutic strategy in aHUS, though current therapies require intravenous administration increase risk infection encapsulated organisms, including meningococcal infection. Further studies are required to define optimal duration existing therapies, identify new...
Anti-VEGF therapy is a clinically validated treatment for age-related macular degeneration (AMD). We have recently reported the discovery of oral VEGFR-2 inhibitors that are selectively distributed to ocular tissues. Herein we report further development those compounds and in particular validation hypothesis aminoheterocycles such as aminoisoxazoles aminopyrazoles could also function effective "hinge" binding moieties leading new class KDR (kinase insert domain containing receptor) inhibitors.
The serine protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form enzyme, FXIa. Herein, we disclose our identify potent, selective, and orally bioavailable inhibitors Compound 1, identified from diverse library internal inhibitors, was originally designed complement D inhibitor exhibited submicromolar FXIa activity encouraging...
Complement factor D (FD), a highly specific S1 serine protease, plays central role in the amplification of alternative complement pathway (AP) innate immune system. Dysregulation AP activity predisposes individuals to diverse disorders such as age-related macular degeneration, atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II, and paroxysmal nocturnal hemoglobinuria. Previously, we have reported screening efforts identification reversible benzylamine-based...
HIV-1 integrase (IN) is an important target for designing new antiviral therapies. Screening of potential inhibitors using recombinant IN-based assays has revealed a number promising leads including nucleotide analogs such as pyridoxal 5′-phosphate (PLP). Certain PLP derivatives were shown to also exhibit activities in cell-based assays. To identify inhibitory binding site IN, we used the intrinsic chemical property this compound form Schiff base with primary amine protein at site. The amino...