Optimization of diarylazines as anti-HIV agents with dramatically

Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.Fil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cisneros, José A.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados Unido

Structure-based evaluation of C5 derivatives in the catechol diether series targeting HIV-1 reverse transcriptase

Using a computationally driven approach, a class of inhibitors with picomolar potency known as the catechol diethers were developed targeting the non-nucleoside-binding pocket of HIV-1 reverse transcriptase. Computational studies suggested that halogen-bonding interactions between the C5 substituent of the inhibitor and backbone carbonyl of conserved residue Pro95 might be important. While the recently reported crystal structures of the reverse transcriptase complexes confirmed the interactions with the non-nucleoside-binding pocket, they revealed the lack of a halogen-bonding interaction with Pro95. To understand the effects of substituents at the C5 position, we determined additional crystal structures with 5-Br and 5-H derivatives. Using comparative structural analysis, we identified several conformations of the ethoxy uracil dependent on the strength of a van der Waals interaction with the Cγ of Pro95 and the C5 substitution. The 5-Cl and 5-F derivatives position the ethoxy uracil to make more hydrogen bonds, whereas the larger 5-Br and smaller 5-H position the ethoxy uracil to make fewer hydrogen bonds. EC50 values correlate with the trends observed in the crystal structures. The influence of C5 substitutions on the ethoxy uracil conformation may have strategic value, as future derivatives can possibly be modulated to gain additional hydrogen-bonding interactions with resistant variants of reverse transcriptase.Fil: Frey, Kathleen M.. University of Yale; Estados UnidosFil: Gray, William T.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gallardo Macias, Ricardo. University of Yale; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados Unido

Structure and Magnetism of Neutral and Anionic Palladium Clusters

The properties of neutral and anionic Pd_N clusters were investigated with spin-density-functional calculations. The ground state structures are three-dimensional for N>3 and they are magnetic with a spin-triplet for 2<=N<=7 and a spin nonet for N=13 neutral clusters. Structural- and spin-isomers were determined and an anomalous increase of the magnetic moment with temperature is predicted for a Pd_7 ensemble. Vertical electron detachment and ionization energies were calculated and the former agree well with measured values for anionic Pd_N clusters.Comment: 5 pages, 3 figures, fig. 2 in color, accepted to Phys. Rev. Lett. (2001

Extension into the entrance channel of HIV-1 reverse transcriptase—Crystallography and enhanced solubility

Non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-RT) are reported that feature extension into the entrance channel near Glu138. Complexes of the parent anilinylpyrimidine 1 and the morpholinoethoxy analog 2j with HIV-RT have received crystallographic characterization confirming the designs. Measurement of aqueous solubilities of 2j, 2k, the parent triazene 2a, and other NNRTIs demonstrate profound benefits for addition of the morpholinyl substituent.Fil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Frey, Kathleen M.. University of Yale. School of Medicine; Estados UnidosFil: Cisneros, José A.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale. School of Medicine; Estados UnidosFil: Das, Kalyan. Rutgers University; Estados UnidosFil: Bauman, Joseph D.. Rutgers University; Estados UnidosFil: Arnold, Eddy. Rutgers University; Estados UnidosFil: Anderson, Karen S.. University of Yale. School of Medicine; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados Unido

Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase

Reverse transcriptase (RT) from the human immunodeficiency virus continues to be an attractive drug target for antiretroviral therapy. June 2022 will commemorate the 30th anniversary of the first Human Immunodeficiency Virus (HIV) RT crystal structure complex that was solved with non-nucleoside reverse transcriptase inhibitor nevirapine. The release of this structure opened opportunities for designing many families of non-nucleoside reverse transcriptase inhibitors (NNRTIs). In paying tribute to the first RT-nevirapine structure, we have developed several compound classes targeting the non-nucleoside inhibitor binding pocket of HIV RT. Extensive analysis of crystal structures of RT in complex with the compounds informed iterations of structure-based drug design. Structures of seven additional complexes were determined and analyzed to summarize key interactions with residues in the non-nucleoside inhibitor binding pocket (NNIBP) of RT. Additional insights comparing structures with antiviral data and results from molecular dynamics simulations elucidate key interactions and dynamics between the nucleotide and non-nucleoside binding sites.Fil: Frey, Kathleen M.. University of Yale; Estados UnidosFil: Bertoletti, Nicole. University of Yale; Estados UnidosFil: Chan, Albert H.. University of Yale; Estados UnidosFil: Ippolito, Joseph A.. University of Yale; Estados UnidosFil: Bollini, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados Unido

GAN-based multiple adjacent brain MRI slice reconstruction for unsupervised alzheimer’s disease diagnosis

Unsupervised learning can discover various unseen diseases, relying on large-scale unannotated medical images of healthy subjects. Towards this, unsupervised methods reconstruct a single medical image to detect outliers either in the learned feature space or from high reconstruction loss. However, without considering continuity between multiple adjacent slices, they cannot directly discriminate diseases composed of the accumulation of subtle anatomical anomalies, such as Alzheimer's Disease (AD). Moreover, no study has shown how unsupervised anomaly detection is associated with disease stages. Therefore, we propose a two-step method using Generative Adversarial Network-based multiple adjacent brain MRI slice reconstruction to detect AD at various stages: (Reconstruction) Wasserstein loss with Gradient Penalty + L1 loss---trained on 3 healthy slices to reconstruct the next 3 ones---reconstructs unseen healthy/AD cases; (Diagnosis) Average/Maximum loss (e.g., L2 loss) per scan discriminates them, comparing the reconstructed/ground truth images. The results show that we can reliably detect AD at a very early stage with Area Under the Curve (AUC) 0.780 while also detecting AD at a late stage much more accurately with AUC 0.917; since our method is fully unsupervised, it should also discover and alert any anomalies including rare disease.Comment: 10 pages, 4 figures, Accepted to Lecture Notes in Bioinformatics (LNBI) as a volume in the Springer serie

UBVRI observations of the flickering of RS Ophiuchi at Quiescence

We report observations of the flickering variability of the recurrent nova RS Oph at quiescence on the basis of simultaneous observations in 5 bands (UBVRI). RS Oph has flickering source with (U-B)_0=-0.62 \pm 0.07, (B-V)_0=0.15 \pm 0.10, (V-R)_0=0.25 \pm 0.05. We find for the flickering source a temperature T_fl = 9500 \pm 500 K, and luminosity L_fl = 50 - 150 L_sun (using a distance of d=1.6kpc). We also find that on a (U-B) vs (B-V) diagram the flickering of the symbiotic stars differs from that of the cataclysmic variables. The possible source of the flickering is discussed. The data are available upon request from the authors and on the web www.astro.bas.bg/~rz/RSOph.UBVRI.2010.MNRAS.tar.gz.Comment: 7 pages, MNRAS (accepted

Distribution, excretion and metabolic pathways of a single parenteral administration of kappa-opioid receptor agonist RU-1205

The purpose was to study the pharmacokinetic properties of RU-1205 with the previously identified kappa-agonistic and analgesic effects after parenteral administratio

Influence of Diazepino [1,2-a] benzimidazole derivative (DAB-19) on behavioral aspects of animals

In the present study, compound DAB-19 was screened for its influence on animals` behavior patterns, such as aggression, obsessive-compulsive behavior, emotional lability, and unsociabilit

Potent inhibitors active against HIV reverse transcriptase with K101P, a mutation conferring rilpivirine resistance

Catechol diether compounds have nanomolar antiviral and enzymatic activity against HIV with reverse transcriptase (RT) variants containing K101P, a mutation that confers high-level resistance to FDA-approved non-nucleoside inhibitors efavirenz and rilpivirine. Kinetic data suggests that RT (K101P) variants are as catalytically fit as wild-type and thus can potentially increase in the viral population as more antiviral regimens include efavirenz or rilpivirine. Comparison of wild-type structures and a new crystal structure of RT (K101P) in complex with a leading compound confirms that the K101P mutation is not a liability for the catechol diethers while suggesting that key interactions are lost with efavirenz and rilpivirine.Fil: Gray, William T.. University of Yale; Estados UnidosFil: Frey, Kathleen M.. University of Yale; Estados UnidosFil: Laskey, Sarah B.. University Johns Hopkins; Estados UnidosFil: Mislak, Andrea C.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Lee, Won Gil. University of Yale; Estados UnidosFil: Bollini, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Yale; Estados UnidosFil: Siliciano, Robert F.. University Johns Hopkins; Estados Unidos. Howard Hughes Medial Institute; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados Unido