Discovery of potential inhibitor against human acetylcholinesterase: a molecular docking and molecular dynamics investigation

Alzheimer’s disease (AD) is a progressive neurodegenerative disease of central nervous system among elderly people. Human acetylcholinesterase (hAChE), an important enzyme in neuronal signaling, is responsible for the degradation of acetylcholine which in turn prevents the post synaptic signal transmissions. hAChE has been an attractive target of drug discovery for the search of therapeutics against AD. In the recent past hAChE has become hot target for the investigation of new potential therapeutics. We performed virtual screening of entire database against hAChE. Further, the extra precision molecular docking was carried out to refine the docking results and the best complex was passed for molecular dynamics simulations in order of understanding the hAChE dynamics and its behavior in complex with the ligand which corroborate the outcomes of virtual screening. This also provides binding free energy data that establishes the ligands efficiency for inhibiting hAChE. The computational findings discussed in this paper provide initial information of inhibitory effects of ligand, (drugbank entry DB00983), over hAChE.     

Virtual screening of B-Raf kinase inhibitors: A combination of pharmacophore modelling,molecular docking, 3D-QSAR model and binding free energy calculation studies

B-Raf kinase has been identified as an important target in recent cancer treatment. In order to discover structurally diverse and novel B-Raf inhibitors (BRIs), a virtual screening of BRIs against ZINC database was performed by using a combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy (ΔG_bind) calculation studies in this work. After the virtual screening, six promising hit compounds were obtained, which were then tested for inhibitory activities of A375 cell lines. In the result, five hit compounds show good biological activities (IC₅₀ < 50 μM). The present method of virtual screening can be applied to find structurally diverse inhibitors, and the obtained five structurally diverse compounds are expected to develop novel BRIs.     

In silico virtual screening of potent inhibitor to hamper the interaction between HIV-1 integrase and LEDGF/p75 interaction using E-pharmacophore modeling,molecular docking,and dynamics simulations

The rapid increase of HIV-1 infection throughout the globe has a high demand for a superior drug with lesser side effects. LEDGF/p75, the human Lens Epithelium-Derived Growth Factor is identified as a promising cellular cofactor with integrase in facilitating the viral replication in an early stage by acting as a tethering factor in the pre-integration to the chromatin. Therefore, the present study was designed to identify a potent inhibitor by applying an E-pharmacophore based virtual screening, molecular docking, and dynamics simulation approaches. Finally, ZINC22077550 and ZINC32124441 were best identified potent molecules with the efficient binding affinity, strong hydrogen bonding, and acceptable pharmacological properties to hamper the interaction between integrase and LEDGF/p75. Further, the DFT and MDS studies were also analyzed, and shown a favorable energetic state and dynamic stability then reference compound. In conclusion, we suggest that these findings could be novel therapeutics in the future and may increase the lifespan of individuals suffering from viral infection.     

Understanding Molecular Dynamics with Stochastic Processes via Real or Virtual Dynamics

Molecular dynamics with the stochastic process provides a convenient way to compute structural and thermodynamic properties of chemical, biological, and materials systems. It is demonstrated that the virtual dynamics case that we proposed for the Langevin equation[J. Chem. Phys. 147 , 184104 (2017)] in principle exists in other types of stochastic thermostats as well. The recommended "middle" scheme[J. Chem. Phys. 147 , 034109 (2017)] of the Andersen thermostat is investigated as an example. As shown by both analytic and numerical results, while the real and virtual dynamics cases approach the same plateau of the characteristic correlation time in the high collision frequency limit, the accuracy and efficiency of sampling are relatively insensitive to the value of the collision frequency in a broad range. After we compare the behaviors of the Andersen thermostat to those of Langevin dynamics, a heuristic schematic representation is proposed for understanding efficient stochastic thermostatting processes with molecular dynamics.     

基于结构虚拟筛选发现蛋白质精氨酸甲基转移酶5抑制剂

蛋白质精氨酸甲基转移酶5(PRMT5)是蛋白质甲基转移酶家族(PRMTs)的重要一员,其主要生理功能是催化精氨酸单对称二甲基化。PRMT5的上调发生在不同类型的肿瘤中,并与不良预后密切相关,已被视为肿瘤治疗中的潜在靶点。近年来,已有多种PRMT5抑制剂进入临床试验,但目前尚未有药物获批上市。本研究基于Glide对接的虚拟筛选和生物活性实验,发现化合物8018-1271对PRMT5酶的抑制活性IC₅₀值为13.56±0.86μmol/L,并通过分子动力学揭示其与PRMT5蛋白结构域的相互作用模式。本研究所得化合物8018-1271可作为进一步改造的先导化合物,为新型PRMT5抑制剂的发现提供参考。     

Statistical inference and modelling of momentum in stock prices

The following results are obtained, (i) It is possible to obtain a time series of market data {y(t)} in which the fluctuations in fundamental value have been compensated for. An objective test of the efficient market hypothesis (EMH), which would predict random correlations about a constant value, is thereby possible, (ii) A time series procedure can be used to determine the extent to which the differences in the data and the moving averages are significant. This provides a model of the form y(t)-y(t-l)=0.5{y(t- l)-y(t-2)}+ε(t)+0.8ε(r-1) where ε(t) is the error at time t, and the coefficients 0.5 and 0.8 are determined from the data. One concludes that today's price is not a random perturbation from yesterday's; rather, yesterday's rate of change is a significant predictor of today's rate of change. This confirms the concept of momentum that is crucial to market participants. (iii) The model provides out-of-sample predictions that can be tested statistically. (iv) The model and coefficients obtained in this way can be used to make predictions on laboratory experiments to establish an objective and quantitative link between the experiments and the market data. These methods circumvent the central difficulty in testing market data, namely, that changes in fundamentals obscure intrinsic trends and autocorrelations. This procedure is implemented by considering the ratio of two similar funds (Germany and Future Germany) with the same manager and performing a set of statistical tests that have excluded fluctuations in fundamental factors. For the entire data of the first 1149 days beginning with the introduction of the latter fund, a standard runs test indicates that the data is 29 standard deviations away from that which would be expected under a hypothesis of random fluctuations about the fundamental value. This and other tests provide strong evidence against the efficient market hypothesis and in favour of autocorrelations in the data. An ARIMA time series finds strong evidence (9.6 and 21.6 standard deviations in the two coefficients) that the data is described by a model that involves the first difference, indicating that momentum is the significant factor. The first quarter's data is used to make out-of-sample predictions for the second quarter with results that are significant to 3 standard deviations. Finally, the ARIMA model and coefficients are used to make predictions on laboratory experiments of Porter and Smith in which the intrinsic value is clear. The model's forecasts are decidedly more accurate than that of the null hypothesis of random fluctuations about the fundamental value.     

On hyperbolic virtual polytopes and hyperbolic fans

Hyperbolic virtual polytopes arose originally as polytopal versions of counterexamples to the following A.D.Alexandrov’s uniqueness conjecture: Let K ⊂ ℝ³ be a smooth convex body. If for a constant C, at every point of ∂K, we have R ₁ ≤ C ≤ R ₂ then K is a ball. (R ₁ and R ₂ stand for the principal curvature radii of ∂K.) This paper gives a new (in comparison with the previous construction by Y.Martinez-Maure and by G.Panina) series of counterexamples to the conjecture. In particular, a hyperbolic virtual polytope (and therefore, a hyperbolic hérisson) with odd an number of horns is constructed. Moreover, various properties of hyperbolic virtual polytopes and their fans are discussed.     

Fluid and diffusion limits for transient sojourn times of processor sharing queues with time varying rates

We provide an approximate analysis of the transient sojourn time for a processor sharing queue with time varying arrival and service rates, where the load can vary over time, including periods of overload. Using the same asymptotic technique as uniform acceleration as demonstrated in [12] and [13], we obtain fluid and diffusion limits for the sojourn time of the M_t/M_t/1 processor-sharing queue. Our analysis is enabled by the introduction of a “virtual customer” which differs from the notion of a “tagged customer” in that the former has no effect on the processing time of the other customers in the system. Our analysis generalizes to non-exponential service and interarrival times, when the fluid and diffusion limits for the queueing process are known.     

A virtual control concept for state constrained optimal control problems

A linear elliptic control problem with pointwise state constraints is considered. These constraints are given in the domain. In contrast to this, the control acts only at the boundary. We propose a general concept using virtual control in this paper. The virtual control is introduced in objective, state equation, and constraints. Moreover, additional control constraints for the virtual control are investigated. An error estimate for the regularization error is derived as main result of the paper. The theory is illustrated by numerical tests.