Inhibition of Cysteine Proteases by 6,6′-Dihydroxythiobinupharidine (DTBN) from Nuphar lutea

The specificity of inhibition by 6,6′-dihydroxythiobinupharidine (DTBN) on cysteine proteases was demonstrated in this work. There were differences in the extent of inhibition, reflecting active site structural-steric and biochemical differences. Cathepsin S (IC₅₀ = 3.2 μM) was most sensitive to inhibition by DTBN compared to Cathepsin B, L and papain (IC₅₀ = 1359.4, 13.2 and 70.4 μM respectively). DTBN is inactive for the inhibition of M^pro of SARS-CoV-2. Docking simulations suggested a mechanism of interaction that was further supported by the biochemical results. In the docking results, it was shown that the cysteine sulphur of Cathepsin S, L and B was in close proximity to the DTBN thiaspirane ring, potentially forming the necessary conditions for a nucleophilic attack to form a disulfide bond. Covalent docking and molecular dynamic simulations were performed to validate disulfide bond formation and to determine the stability of Cathepsins-DTBN complexes, respectively. The lack of reactivity of DTBN against SARS-CoV-2 M^pro was attributed to a mismatch of the binding conformation of DTBN to the catalytic binding site of M^pro. Thus, gradations in reactivity among the tested Cathepsins may be conducive for a mechanism-based search for derivatives of nupharidine against COVID-19. This could be an alternative strategy to the large-scale screening of electrophilic inhibitors.     

Undecidability of pseudop-adically closed fields

The content of this paper corresponds to a part of the author's Ph.D. thesis carried out in Tel Aviv University under the supervision of Prof. Moshe Jarden. The work was partially supported by a grant from the G.I.F., the German-Israeli Foundation for Scientific Research and Development.     

Intrinsic fluorescence polarization of amniotic fluid: evaluation of human fetal lung maturity

This article reports a novel approach for the evaluation of fetal lung maturity based on fluorescence polarization (FP). The technique determines the intrinsic fluorescence polarization ratio (IFPR) of the amniotic fluid (AF). In vitro measurements of the IFPR indicate a clear dichotomy: high values for young pregnancies and low values for mature pregnancies. The new method has the potential to be a noninvasive procedure because the excitation of the AF and the collection of its fluorescence emission can be performed through the intact cervical amniotic membranes.     

Experimental estimates of dephasing time in molecular magnets

Muon spin relaxation measurements in isotropic molecular magnets (MM) with a spin value S ranging from 7/2 to 27/2 are used to determine the magnitude and origin of dephasing time tau(phi) of molecular magnets. It is found that tau(phi) approximately 10 nsec with no S or ligand dependence. This indicates a nuclear origin for the stochastic field. Since tau(phi) is a property of the environment, we argue that it is a number common to similar types of MM. Therefore, tau(phi) is shorter than the Zener and tunneling times of anisotropic MM such as Fe(8) or Mn(4) for standard laboratory sweep rates. Our findings call for a stochastic Landau-Zener theory in this particular case.     

Geometric Pattern Matching in d -Dimensional Space

We show that, using the L _∞ metric, the minimum Hausdorff distance under translation between two point sets of cardinality n in d -dimensional space can be computed in time O(n ^(4d-2)/3 log ² n) for 3 < d 8, and in time O(n ^5d/4 log ² n) for any d > 8 . Thus we improve the previous time bound of O(n ^2d-2 log ² n) due to Chew and Kedem. For d=3 we obtain a better result of O(n ³ log ² n) time by exploiting the fact that the union of n axis-parallel unit cubes can be decomposed into O(n) disjoint axis-parallel boxes. We prove that the number of different translations that achieve the minimum Hausdorff distance in d -space is . Furthermore, we present an algorithm which computes the minimum Hausdorff distance under the L ₂ metric in d -space in time , for any δ > 0. Received March 17, 1997, and in revised form January 19, 1998.     

Exact analysis for multiserver queueing systems with cross selling

Annals of Operations Research - Exact analysis of a multi-server Markovian queueing system with cross selling in steady-state is presented. Cross selling attempt is initiated at the end of a...     

Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening

Folding correctors of F508del-CFTR were discovered by in silico structure-based screening utilizing homology models of CFTR. The intracellular segment of CFTR was modeled and three cavities were identified at inter-domain interfaces: (1) Interface between the two Nucleotide Binding Domains (NBDs); (2) Interface between NBD1 and Intracellular Loop (ICL) 4, in the region of the F508 deletion; (3) multi-domain interface between NBD1:2:ICL1:2:4. We hypothesized that compounds binding at these interfaces may improve the stability of the protein, potentially affecting the folding yield or surface stability. In silico structure-based screening was performed at the putative binding-sites and a total of 496 candidate compounds from all three sites were tested in functional assays. A total of 15 compounds, representing diverse chemotypes, were identified as F508del folding correctors. This corresponds to a 3% hit rate, ~tenfold higher than hit rates obtained in corresponding high-throughput screening campaigns. The same binding sites also yielded potentiators and, most notably, compounds with a dual corrector-potentiator activity (dual-acting). Compounds harboring both activity types may prove to be better leads for the development of CF therapeutics than either pure correctors or pure potentiators. To the best of our knowledge this is the first report of structure-based discovery of CFTR modulators.     

Flexible protein‐protein docking based on Best‐First search algorithm

We developed a new high resolution protein‐protein docking method based on Best‐First search algorithm that loosely imitates protein‐protein associations. The method operates in two stages: first, we perform a rigid search on the unbound proteins. Second, we search alternately on rigid and flexible degrees of freedom starting from multiple configurations from the rigid search. Both stages use heuristics added to the energy function, which causes the proteins to rapidly approach each other and remain adjacent, while optimizing on the energy. The method deals with backbone flexibility explicitly by searching over ensembles of conformations generated before docking. We ran the rigid docking stage on 66 complexes and grouped the results into four classes according to evaluation criteria used in Critical Assessment of Predicted Interactions (CAPRI; “high,” “medium,” “acceptable,” and “incorrect”). Our method found medium binding conformations for 26% of the complexes and acceptable for additional 44% among the top 10 configurations. Considering all the configurations, we found medium binding conformations for 55% of the complexes and acceptable for additional 39% of the complexes. Introducing side‐chains flexibility in the second stage improves the best found binding conformation but harms the ranking. However, introducing side‐chains and backbone flexibility improve both the best found binding conformation and the best found conformation in the top 10. Our approach is a basis for incorporating multiple flexible motions into protein‐protein docking and is of interest even with the current use of a simple energy function. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

On the Complexity of the Union of Fat Convex Objects in the Plane

We prove a near-linear bound on the combinatorial complexity of the union of n fat convex objects in the plane, each pair of whose boundaries cross at most a constant number of times. Received April 7, 1998, and in revised form August 24, 1999.