Fragment Screening in the Development of a Novel Anti-Malarial

Fragment-based approaches offer rapid screening of chemical space and have become a mainstay in drug discovery. This manuscript provides a recent example that highlights the initial and intermediate stages involved in the fragment-based discovery of an allosteric inhibitor of the malarial aspartate transcarbamoylase (ATCase), subsequently shown to be a potential novel anti-malarial. The initial availability of high-resolution diffracting crystals allowed the collection of a number of protein fragment complexes, which were then assessed for inhibitory activity in an in vitro assay, and binding was assessed using biophysical techniques. Elaboration of these compounds in cycles of structure-based drug design improved activity and selectivity between the malarial and human ATCases. A key element in this process was the use of multicomponent reaction chemistry as a multicomponent compatible fragment library, which allowed the rapid generation of elaborated compounds, the rapid construction of a large (70 member) chemical library, and thereby efficient exploration of chemical space around the fragment hits. This review article details the steps along the pathway of the development of this library, highlighting potential limitations of the approach and serving as an example of the power of combining multicomponent reaction chemistry with fragment-based approaches.</p

Fragment Screening in the Development of a Novel Anti-Malarial

Fragment-based approaches offer rapid screening of chemical space and have become a mainstay in drug discovery. This manuscript provides a recent example that highlights the initial and intermediate stages involved in the fragment-based discovery of an allosteric inhibitor of the malarial aspartate transcarbamoylase (ATCase), subsequently shown to be a potential novel anti-malarial. The initial availability of high-resolution diffracting crystals allowed the collection of a number of protein fragment complexes, which were then assessed for inhibitory activity in an in vitro assay, and binding was assessed using biophysical techniques. Elaboration of these compounds in cycles of structure-based drug design improved activity and selectivity between the malarial and human ATCases. A key element in this process was the use of multicomponent reaction chemistry as a multicomponent compatible fragment library, which allowed the rapid generation of elaborated compounds, the rapid construction of a large (70 member) chemical library, and thereby efficient exploration of chemical space around the fragment hits. This review article details the steps along the pathway of the development of this library, highlighting potential limitations of the approach and serving as an example of the power of combining multicomponent reaction chemistry with fragment-based approaches.</p

High cholesterol level upregulate the expression of caveolin-1

2004-2005 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

B(s)0B^0_{(s)}-mixing matrix elements from lattice QCD for the Standard Model and beyond

We calculate---for the first time in three-flavor lattice QCD---the hadronic matrix elements of all five local operators that contribute to neutral $B^0$- and $B_s$-meson mixing in and beyond the Standard Model. We present a complete error budget for each matrix element and also provide the full set of correlations among the matrix elements. We also present the corresponding bag parameters and their correlations, as well as specific combinations of the mixing matrix elements that enter the expression for the neutral $B$-meson width difference. We obtain the most precise determination to date of the SU(3)-breaking ratio $\xi = 1.206(18)(6)$, where the second error stems from the omission of charm sea quarks, while the first encompasses all other uncertainties. The threefold reduction in total uncertainty, relative to the 2013 Flavor Lattice Averaging Group results, tightens the constraint from $B$ mixing on the Cabibbo-Kobayashi-Maskawa (CKM) unitarity triangle. Our calculation employs gauge-field ensembles generated by the MILC Collaboration with four lattice spacings and pion masses close to the physical value. We use the asqtad-improved staggered action for the light valence quarks, and the Fermilab method for the bottom quark. We use heavy-light meson chiral perturbation theory modified to include lattice-spacing effects to extrapolate the five matrix elements to the physical point. We combine our results with experimental measurements of the neutral $B$-meson oscillation frequencies to determine the CKM matrix elements $|V_{td}| = 8.00(34)(8) \times 10^{-3}$, $|V_{ts}| = 39.0(1.2)(0.4) \times 10^{-3}$, and $|V_{td}/V_{ts}| = 0.2052(31)(10)$, which differ from CKM-unitarity expectations by about 2$\sigma$. These results and others from flavor-changing-neutral currents point towards an emerging tension between weak processes that are mediated at the loop and tree levels.Comment: 75 pp, 17 figs. Ver 2 fixes typos; corrects mistakes resulting in slight changes to results, correlation matrices; updates decay constants to agree with recent PDG update; corrects uncertainties for tree-level CKM matrix elements used in comparison, slightly reducing tensions; includes additional analyses that support mostly-nonperturbative matching; expands discussion of isospin-breaking effect

B_s->D_s/B->D Semileptonic Form-Factor Ratios and Their Application to BR(B^0_s->\mu^+\mu^-)

We calculate form-factor ratios between the semileptonic decays \bar{B}->D^+\ell^-\bar{\nu} and \bar{B}_s->D_s^+\ell^-\bar{\nu} with lattice QCD. These ratios are a key theoretical input in a new strategy to determine the fragmentation fractions of the neutral B decays, which are needed for measurements of BR(B^0_s-> \mu^+\mu^-). We use the MILC ensembles of gauge configurations with 2+1 flavors of sea quarks at two lattice spacings of approximately 0.12 fm and 0.09 fm. We use the model-independent z-parametrization to extrapolate our simulation results at small recoil toward maximum recoil. Our results for the form-factor ratios are $f_0^{(s)}(M^2_\pi)/f_0^{(d)}(M^2_K) =1.046(44)_{stat.}(15)_{syst.}$ and $f_0^{(s)}(M^2_\pi)/f_0^{(d)}(M^2_\pi)=1.054(47)_{stat.}(17)_{syst.}$. In contrast to a QCD sum-rule calculation, no significant departure from U-spin (ds) symmetry is observed.Comment: 30 pages, 11 figures. Fig. 1 updated. Table II added. Conforms with version published in Physical Review D, except typos fixed, as in the PRD Erratum, in Table V (previously Table IV in arXiv v1). Results unchange

Bs→KℓνB_s \to K \ell\nu form factors with 2+1 flavors

Using the MILC 2+1 flavor asqtad quark action ensembles, we are calculating the form factors $f_0$ and $f_+$ for the semileptonic $B_s \rightarrow K \ell\nu$ decay. A total of six ensembles with lattice spacing from $\approx0.12$ to 0.06 fm are being used. At the coarsest and finest lattice spacings, the light quark mass $m'_l$ is one-tenth the strange quark mass $m'_s$. At the intermediate lattice spacing, the ratio $m'_l/m'_s$ ranges from 0.05 to 0.2. The valence $b$ quark is treated using the Sheikholeslami-Wohlert Wilson-clover action with the Fermilab interpretation. The other valence quarks use the asqtad action. When combined with (future) measurements from the LHCb and Belle II experiments, these calculations will provide an alternate determination of the CKM matrix element $|V_{ub}|$.Comment: 8 pages, 6 figures, to appear in the Proceedings of Lattice 2017, June 18-24, Granada, Spai

Update of ∣Vcb∣|V_{cb}| from the Bˉ→D∗ℓνˉ\bar{B}\to D^*\ell\bar{\nu} form factor at zero recoil with three-flavor lattice QCD

We compute the zero-recoil form factor for the semileptonic decay $\bar{B}^0\to D^{*+}\ell^-\bar{\nu}$ (and modes related by isospin and charge conjugation) using lattice QCD with three flavors of sea quarks. We use an improved staggered action for the light valence and sea quarks (the MILC \asqtad\ configurations), and the Fermilab action for the heavy quarks. Our calculations incorporate higher statistics, finer lattice spacings, and lighter quark masses than our 2008 work. As a byproduct of tuning the new data set, we obtain the $D_s$ and $B_s$ hyperfine splittings with few-MeV accuracy. For the zero-recoil form factor, we obtain $\mathcal{F}(1)=0.906(4)(12)$, where the first error is statistical and the second is the sum in quadrature of all systematic errors. With the latest HFAG average of experimental results and a cautious treatment of QED effects, we find $|V_{cb}| = (39.04 \pm 0.49_\text{expt} \pm 0.53_\text{QCD} \pm 0.19_\text{QED})\times10^{-3}$. The QCD error is now commensurate with the experimental error.Comment: 53 pages, 12 figures; expanded discussion of correlator fits, typos corrected, conforms to version published in PR

B→Kl+l−B\to Kl^+l^- decay form factors from three-flavor lattice QCD

We compute the form factors for the $B \to Kl^+l^-$ semileptonic decay process in lattice QCD using gauge-field ensembles with 2+1 flavors of sea quark, generated by the MILC Collaboration. The ensembles span lattice spacings from 0.12 to 0.045 fm and have multiple sea-quark masses to help control the chiral extrapolation. The asqtad improved staggered action is used for the light valence and sea quarks, and the clover action with the Fermilab interpretation is used for the heavy $b$ quark. We present results for the form factors $f_+(q^2)$, $f_0(q^2)$, and $f_T(q^2)$, where $q^2$ is the momentum transfer, together with a comprehensive examination of systematic errors. Lattice QCD determines the form factors for a limited range of $q^2$, and we use the model-independent $z$ expansion to cover the whole kinematically allowed range. We present our final form-factor results as coefficients of the $z$ expansion and the correlations between them, where the errors on the coefficients include statistical and all systematic uncertainties. We use this complete description of the form factors to test QCD predictions of the form factors at high and low $q^2$. We also compare a Standard-Model calculation of the branching ratio for $B \to Kl^+l^-$ with experimental data.Comment: V2: Fig.7 added. Typos text corrected. Reference added. Version published in Phys. Rev.