Investigating the Molecular Basis of N-Substituted 1-Hydroxy-4-Sulfamoyl-2-Naphthoate Compounds Binding to Mcl1

Myeloid cell leukemia-1 (Mcl1) is an anti-apoptotic protein that has gained considerable attention due to its overexpression activity prevents cell death. Therefore, a potential inhibitor that specifically targets Mcl1 with higher binding affinity is necessary. Recently, a series of N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoate compounds was reported that targets Mcl1, but its binding mechanism remains unexplored. Here, we attempted to explore the molecular mechanism of binding to Mcl1 using advanced computational approaches: pharmacophore-based 3D-QSAR, docking, and MD simulation. The selected pharmacophoreNNRRRyielded a statistically significant 3D-QSAR model containing high confidence scores (R-2 = 0.9209, Q(2) = 0.8459, and RMSE = 0.3473). The contour mapscomprising hydrogen bond donor, hydrophobic, negative ionic and electron withdrawal effectsfrom our 3D-QSAR model identified the favorable regions crucial for maximum activity. Furthermore, the external validation of the selected model using enrichment and decoys analysis reveals a high predictive power. Also, the screening capacity of the selected model had scores of 0.94, 0.90, and 8.26 from ROC, AUC, and RIE analysis, respectively. The molecular docking of the highly active compoundC40; 4-(N-benzyl-N-(4-(4-chloro-3,5-dimethylphenoxy) phenyl) sulfamoyl)-1-hydroxy-2-naphthoatepredicted the low-energy conformational pose, and the MD simulation revealed crucial details responsible for the molecular mechanism of binding with Mcl1

Thermalization from gauge/gravity duality: Evolution of singularities in unequal time correlators

We consider a gauge/gravity dual model of thermalization which consists of a collapsing thin matter shell in asymptotically Anti-de Sitter space. A central aspect of our model is to consider a shell moving at finite velocity as determined by its equation of motion, rather than a quasi-static approximation as considered previously in the literature. By applying a divergence matching method, we obtain the evolution of singularities in the retarded unequal time correlator $G^R(t,t')$, which probes different stages of the thermalization. We find that the number of singularities decreases from a finite number to zero as the gauge theory thermalizes. This may be interpreted as a sign of decoherence. Moreover, in a second part of the paper, we show explicitly that the thermal correlator is characterized by the existence of singularities in the complex time plane. By studying a quasi-static state, we show the singularities at real times originate from contributions of normal modes. We also investigate the possibility of obtaining complex singularities from contributions of quasi-normal modes.Comment: 35 pages, 4 figure

Mixed RG Flows and Hydrodynamics at Finite Holographic Screen

We consider quark-gluon plasma with chemical potential and study renormalization group flows of transport coefficients in the framework of gauge/gravity duality. We first study them using the flow equations and compare the results with hydrodynamic results by calculating the Green functions on the arbitrary slice. Two results match exactly. Transport coefficients at arbitrary scale is ontained by calculating hydrodynamics Green functions. When either momentum or charge vanishes, transport coefficients decouple from each other.Comment: 22 pages, 6 figure

Compactification on negatively curved manifolds

We show that string/M theory compactifications to maximally symmetric space-times using manifolds whose scalar curvature is everywhere negative, must have significant warping, large stringy corrections, or both.Comment: 18 pages, JHEP3.cl

Holographic dilepton production in a thermalizing plasma

We determine the out-of-equilibrium production rate of dileptons at rest in strongly coupled N=4 Super Yang-Mills plasma using the AdS/CFT correspondence. Thermalization is achieved via the gravitational collapse of a thin shell of matter in AdS_5 space and the subsequent formation of a black hole, which we describe in a quasistatic approximation. Prior to thermalization, the dilepton spectral function is observed to oscillate as a function of frequency, but the amplitude of the oscillations decreases when thermal equilibrium is approached. At the same time, we follow the flow of the quasinormal spectrum of the corresponding U(1) vector field towards its equilibrium limit.Comment: 21 pages, 7 figures. v2: Version accepted for publication in JHEP; minor modifications, added reference

Pathologies in Asymptotically Lifshitz Spacetimes

There has been significant interest in the last several years in studying possible gravitational duals, known as Lifshitz spacetimes, to anisotropically scaling field theories by adding matter to distort the asymptotics of an AdS spacetime. We point out that putative ground state for the most heavily studied example of such a spacetime, that with a flat spatial section, suffers from a naked singularity and further point out this singularity is not resolvable by any known stringy effect. We review the reasons one might worry that asymptotically Lifshitz spacetimes are unstable and employ the initial data problem to study the stability of such systems. Rather surprisingly this question, and even the initial value problem itself, for these spacetimes turns out to generically not be well-posed. A generic normalizable state will evolve in such a way to violate Lifshitz asymptotics in finite time. Conversely, enforcing the desired asymptotics at all times puts strong restrictions not just on the metric and fields in the asymptotic region but in the deep interior as well. Generically, even perturbations of the matter field of compact support are not compatible with the desired asymptotics.Comment: 36 pages, 1 figure, v2: Enhanced discussion of singularity, including relationship to Gubser's conjecture and singularity in RG flow solution, plus minor clarification

Holographic Brownian Motion in Magnetic Environments

Using the gauge/gravity correspondence, we study the dynamics of a heavy quark in two strongly-coupled systems at finite temperature: Super-Yang-Mills in the presence of a magnetic field and non-commutative Super-Yang-Mills. In the former, our results agree qualitatively with the expected behavior from weakly-coupled theories. In the latter, we propose a Langevin equation that accounts for the effects of non-commutativity and we find new interesting features. The equation resembles the structure of Brownian motion in the presence of a magnetic field and implies that the fluctuations along non-commutative directions are correlated. Moreover, our results show that the viscosity is smaller than the commutative case and that the diffusion properties of the quark are unaffected by non-commutativity. Finally, we compute the random force autocorrelator and verify that the fluctuation-dissipation theorem holds in the presence of non-commutativity.Comment: 34 pages. v2: typos corrected. v3: title and abstract slightly modified in order to better reflect the contents of the paper; footnote 3 and one reference were also added; version accepted for publication in JHE

Non-Perturbative Superpotentials in F-theory and String Duality

We use open-closed string duality between F-theory on K3xK3 and type II strings on CY manifolds without branes to study non-perturbative superpotentials in generalized flux compactifications. On the F-theory side we obtain the full flux potential including D3-instanton contributions and show that it leads to an explicit and simple realization of the three ingredients of the KKLT model for stringy dS vacua. The D3-instanton contribution is highly non-trivial, can be systematically computed including the determinant factors and demonstrates that a particular flux lifts very effectively zero modes on the instanton. On the closed string side, we propose a generalization of the Gukov-Vafa-Witten superpotential for type II strings on generalized CY manifolds, depending on all moduli multiplets.Comment: 49 pages, harvmac, 1 figure; references & figures adde

Shear Modes, Criticality and Extremal Black Holes

We consider a (2+1)-dimensional field theory, assumed to be holographically dual to the extremal Reissner-Nordstrom AdS(4) black hole background, and calculate the retarded correlators of charge (vector) current and energy-momentum (tensor) operators at finite momentum and frequency. We show that, similar to what was observed previously for the correlators of scalar and spinor operators, these correlators exhibit emergent scaling behavior at low frequency. We numerically compute the electromagnetic and gravitational quasinormal frequencies (in the shear channel) of the extremal Reissner-Nordstrom AdS(4) black hole corresponding to the spectrum of poles in the retarded correlators. The picture that emerges is quite simple: there is a branch cut along the negative imaginary frequency axis, and a series of isolated poles corresponding to damped excitations. All of these poles are always in the lower half complex frequency plane, indicating stability. We show that this analytic structure can be understood as the proper limit of finite temperature results as T is taken to zero holding the chemical potential fixed.Comment: 28 pages, 7 figures, added reference

Multi-scalar tachyon potential on non-BPS domain walls

We have considered the multi-scalar and multi-tachyon fields living on a 3d domain wall embedded in a 5d dimensional Minkowski spacetime. The effective action for such a domain wall can be found by integrating out the normal modes as vibrating modes around the domain wall solution of a truncated 5d supergravity action. The multi-scalar tachyon potential are good enough to modeling assisted inflation scenario with multi-tachyon fields. The tachyon condensation are also briefly addressed.Comment: version to appear in JHEP, 18 pages, 3 figure