11 research outputs found
TRANSFER LEARNING FOR RESOLVING SPARSITY PROBLEM IN RECOMMENDER SYSTEMS: HUMAN VALUES APPROACH
<div><p>ABSTRACT With the rapid rise in popularity of ecommerce application, Recommender Systems are being widely used by them to predict the response that a user will give to a given item. This prediction helps in cross selling, upselling and to increase the loyalty of their customers. However due to lack of sufficient feedback data these systems suffer from sparsity problem which leads to decline in their prediction efficiency. In this work, we have proposed and empirically demonstrated how the Transfer Learning approach using five dimensions of basic human values can be successfully used to alleviate the sparsity problem and increase the efficiency of recommender system algorithms.</p></div
Evaluation of the metabolism, bioactivation and pharmacokinetics of triaminopyrimidine analogs toward selection of a potential candidate for antimalarial therapy
<p>1. During the course of metabolic profiling of lead Compound <b>1</b>, glutathione (GSH) conjugates were detected in rat bile, suggesting the formation of reactive intermediate precursor(s). This was confirmed by the identification of GSH and <i>N</i>-acetylcysteine (NAC) conjugates in microsomal incubations.</p> <p>2. It was proposed that bioactivation of Compound <b>1</b> occurs via the formation of a di-iminoquinone reactive intermediate through the involvement of the C-2 and C-5 nitrogens of the pyrimidine core.</p> <p>3. To further investigate this hypothesis, structural analogs with modifications at the C-5 nitrogen were studied for metabolic activation in human liver microsomes supplemented with GSH/NAC.</p> <p>4. Compounds <b>1</b> and <b>2</b>, which bear secondary nitrogens at the C-5 of the pyrimidine core, were observed to form significant amounts of GSH/NAC-conjugates <i>in vitro</i>, whereas compounds with tertiary nitrogens at C-5 (Compound <b>3</b> and <b>4</b>) formed no such conjugates.</p> <p>5. These observations provide evidence that electron/hydrogen abstraction is required for the bioactivation of the triaminopyrimidines, potentially via a di-iminoquinone intermediate. The lack of a hydrogen and/or steric hindrance rendered Compound <b>3</b> and <b>4</b> incapable of forming thiol conjugates.</p> <p>6. This finding enabled advancement of compound <b>4</b>, with a desirable potency, safety and PK profile, as a lead candidate for further development in the treatment of malaria.</p
Structural and Functional Insights into the Regulation of <i>Helicobacter pylori</i> Arginase Activity by an Evolutionary Nonconserved Motif
Urea producing bimetallic arginases are essential for
the synthesis
of polyamine, DNA, and RNA. Despite conservation of the signature
motifs in all arginases, a nonconserved <sup>153</sup>ESEEKAWQKLCSL<sup>165</sup> motif is found in the <i>Helicobacter pylori</i> enzyme, whose role is yet unknown. Using site-directed mutagenesis,
kinetic assays, metal analyses, circular dichroism, heat-induced denaturation,
molecular dynamics simulations and truncation studies, we report here
the significance of this motif in catalytic function, metal retention,
structural integrity, and stability of the protein. The enzyme did
not exhibit detectable activity upon deletion of the motif as well
as on individual mutation of Glu155 and Trp159 while Cys163Ala displayed
significant decrease in the activity. Trp159Ala and Glu155Ala show
severe loss of thermostability (14–17°) by a decrease
in the α-helical structure. The role of Trp159 in stabilization
of the structure with the surrounding aromatic residues is confirmed
when Trp159Phe restored the structure and stability substantially
compared to Trp159Ala. The simulation studies support the above results
and show that the motif, which was previously solvent exposed, displays
a loop-cum-small helix structure (Lys161–Cys163) and is located
near the active-site through a novel Trp159–Asp126 interaction.
This is consistent with the mutational analyses, where Trp159 and
Asp126 are individually critical for retaining a bimetallic center
and thereby for function. Furthermore, Cys163 of the helix is primarily
important for dimerization, which is crucial for stimulation of the
activity. Thus, these findings not only provide insights into the
role of this motif but also offer a possibility to engineer it in
human arginases for therapeutics against a number of carcinomas
Media 1: Liquid crystal gratings based on alternate TN and PA photoalignment
Originally published in Optics Express on 27 February 2012 (oe-20-5-5384
Media 2: Liquid crystal gratings based on alternate TN and PA photoalignment
Originally published in Optics Express on 27 February 2012 (oe-20-5-5384
Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting <i>Plasmodium falciparum</i> Type II NADH:Quinone Oxidoreductase (PfNDH2)
A program was undertaken to identify hit compounds against
NADH:ubiquinone
oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron
transport chain of the malaria parasite <i>Plasmodium falciparum</i>. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone
(HDQ), and this was used along with a range of chemoinformatics methods
in the rational selection of 17 000 compounds for high-throughput
screening. Twelve distinct chemotypes were identified and briefly
examined leading to the selection of the quinolone core as the key
target for structure–activity relationship (SAR) development.
Extensive structural exploration led to the selection of 2-bisaryl
3-methyl quinolones as a series for further biological evaluation.
The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one
(CK-2-68) has antimalarial activity against the 3D7 strain of <i>P. falciparum</i> of 36 nM, is selective for PfNDH2 over other
respiratory enzymes (inhibitory IC<sub>50</sub> against PfNDH2 of
16 nM), and demonstrates low cytotoxicity and high metabolic stability
in the presence of human liver microsomes. This lead compound and
its phosphate pro-drug have potent in vivo antimalarial activity after
oral administration, consistent with the target product profile of
a drug for the treatment of uncomplicated malaria. Other quinolones
presented (e.g., <b>6d</b>, <b>6f</b>, <b>14e</b>) have the capacity to inhibit both PfNDH2 and <i>P. falciparum</i> cytochrome <i>bc</i><sub>1</sub>, and studies to determine
the potential advantage of this dual-targeting effect are in progress
Identification, Design and Biological Evaluation of Heterocyclic Quinolones Targeting <i>Plasmodium falciparum</i> Type II NADH:Quinone Oxidoreductase (PfNDH2)
Following a program undertaken to identify hit compounds
against
NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within
the malaria parasite <i>Plasmodium falciparum</i>, hit to
lead optimization led to identification of CK-2-68, a molecule suitable
for further development. In order to reduce ClogP and improve solubility
of CK-2-68 incorporation of a variety of heterocycles, within the
side chain of the quinolone core, was carried out, and this approach
led to a lead compound SL-2-25 (<b>8b</b>). <b>8b</b> has
IC<sub>50</sub>s in the nanomolar range versus both the enzyme and whole cell <i>P. falciparum</i> (IC<sub>50</sub> = 15 nM PfNDH2; IC<sub>50</sub> = 54 nM (3D7 strain
of <i>P. falciparum</i>) with notable oral activity of ED<sub>50</sub>/ED<sub>90</sub> of 1.87/4.72 mg/kg versus <i>Plasmodium
berghei</i> (NS Strain) in a murine model of malaria when formulated
as a phosphate salt. Analogues in this series also demonstrate nanomolar
activity against the <i>bc</i><sub>1</sub> complex of <i>P. falciparum</i> providing the potential added benefit of a
dual mechanism of action. The potent oral activity of 2-pyridyl quinolones
underlines the potential of this template for further lead optimization
studies
Lead Optimization of 1,4-Azaindoles as Antimycobacterial Agents
In a previous
report, we described the discovery of 1,4-azaindoles, a chemical series
with excellent in vitro and in vivo antimycobacterial potency through
noncovalent inhibition of decaprenylphosphoryl-β-d-ribose-2′-epimerase
(DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase
6 (PDE6) off-target activity limited its advancement. Herein, we report
lead optimization of this series, culminating in potent, metabolically
stable compounds that have a robust pharmacokinetic profile without
any PDE6 liability. Furthermore, we demonstrate efficacy for 1,4-azaindoles
in a rat chronic TB infection model. We believe that compounds from
the 1,4-azaindole series are suitable for in vivo combination and
safety studies
<i>N</i>‑Aryl-2-aminobenzimidazoles: Novel, Efficacious, Antimalarial Lead Compounds
From
the phenotypic screening of the AstraZeneca corporate compound
collection, <i>N</i>-aryl-2-aminobenzimidazoles have emerged
as novel hits against the asexual blood stage of <i>Plasmodium
falciparum</i> (<i>Pf</i>). Medicinal chemistry optimization
of the potency against <i>Pf</i> and ADME properties resulted
in the identification of <b>12</b> as a lead molecule. Compound <b>12</b> was efficacious in the <i>P. berghei</i> (<i>Pb</i>) model of malaria. This compound displayed an excellent
pharmacokinetic profile with a long half-life (19 h) in rat blood.
This profile led to an extended survival of animals for over 30 days
following a dose of 50 mg/kg in the <i>Pb</i> malaria model.
Compound <b>12</b> retains its potency against a panel of <i>Pf</i> isolates with known mechanisms of resistance. The fast
killing observed in the <i>in vitro</i> parasite reduction
ratio (PRR) assay coupled with the extended survival highlights the
promise of this novel chemical class for the treatment of malaria
Azaindoles: Noncovalent DprE1 Inhibitors from Scaffold Morphing Efforts, Kill Mycobacterium tuberculosis and Are Efficacious <i>in Vivo</i>
We report 1,4-azaindoles as a new
inhibitor class that kills Mycobacterium tuberculosis <i>in vitro</i> and demonstrates efficacy in mouse tuberculosis
models. The series emerged from scaffold morphing efforts and was
demonstrated to noncovalently inhibit decaprenylphosphoryl-β-d-ribose2′-epimerase (DprE1). With “drug-like”
properties and no expectation of pre-existing resistance in the clinic,
this chemical class has the potential to be developed as a therapy
for drug-sensitive and drug-resistant tuberculosis