Structure-based inhibitor design and repurposing clinical drugs to target SARS-CoV-2 proteases

SARS-CoV-2, the coronavirus responsible for the current COVID-19 pandemic, encodes two proteases, 3CLpro and PLpro, two of the main antiviral research targets. Here we provide an overview of the structures and functions of 3CLpro and PLpro and examine strategies of structure-based drug designing and drug repurposing against these proteases. Rational structure-based drug design enables the generation of potent and target-specific antivirals. Drug repurposing offers an attractive prospect with an accelerated turnaround. Thus far, several protease inhibitors have been identified, and some candidates are undergoing trials that may well prove to be effective antivirals against SARS-CoV-2.

$$\alpha $$-Modulation Spaces for Step Two Stratified Lie Groups

We define and investigate $$\alpha $$ α -modulation spaces $$M_{p,q}^{s,\alpha }(G)$$ M p , q s , α ( G ) associated to a step two stratified Lie group G with rational structure constants. This is an extension of the Euclidean $$\alpha $$ α -modulation spaces $$M_{p,q}^{s,\alpha }({\mathbb {R}}^n)$$ M p , q s , α ( R n ) that act as intermediate spaces between the modulation spaces ($$\alpha = 0$$ α = 0 ) in time-frequency analysis and the Besov spaces ($$\alpha = 1$$ α = 1 ) in harmonic analysis. We will illustrate that the group structure and dilation structure on G affect the boundary cases $$\alpha = 0,1$$ α = 0 , 1 where the spaces $$M_{p,q}^{s}(G)$$ M p , q s ( G ) and $${\mathcal {B}}_{p,q}^{s}(G)$$ B p , q s ( G ) have non-standard translation and dilation symmetries. Moreover, we show that the spaces $$M_{p,q}^{s,\alpha }(G)$$ M p , q s , α ( G ) are non-trivial and generally distinct from their Euclidean counterparts. Finally, we examine how the metric geometry of the coverings $${\mathcal {Q}}(G)$$ Q ( G ) underlying the $$\alpha = 0$$ α = 0 case $$M_{p,q}^{s}(G)$$ M p , q s ( G ) allows for the existence of geometric embeddings $$\begin{aligned} F:M_{p,q}^{s}({\mathbb {R}}^k) \longrightarrow {} M_{p,q}^{s}(G), \end{aligned}$$ F : M p , q s ( R k ) ⟶ M p , q s ( G ) , as long as k (that only depends on G) is small enough. Our approach naturally gives rise to several open problems that is further elaborated at the end of the paper.

The Kynurenine Pathway and Kynurenine 3-Monooxygenase Inhibitors

Under normal physiological conditions, the kynurenine pathway (KP) plays a critical role in generating cellular energy and catabolizing tryptophan. Under inflammatory conditions, however, there is an upregulation of the KP enzymes, particularly kynurenine 3-monooxygenase (KMO). KMO has garnered much attention due to its production of toxic metabolites that have been implicated in many diseases and disorders. With many of these illnesses having an inadequate or modest treatment, there exists a need to develop KMO inhibitors that reduce the production of these toxic metabolites. Though prior efforts to find an appropriate KMO inhibitor were unpromising, the development of a KMO crystal structure has provided the opportunity for a rational structure-based design in the development of inhibitors. Therefore, the purpose of this review is to describe the kynurenine pathway, the kynurenine 3-monooxygenase enzyme, and KMO inhibitors and their potential candidacy for clinical use.

Mixed Fuzzy-Logic and Game-Theoretical Approach to Justify Vehicle Models for Servicing the Public Bus Line

One of the main problems to be solved by the transport operators is the substantiation of the vehicle models servicing the transport lines. A gametheoretical approach is proposed in this paper to justify the bus model choice based on the passengers’ preferences and the structure of the passenger flows. To estimate the customers’ preferences, the membership functions for fuzzy sets of the optimal vehicle models were defined. The simulation experiment aiming to estimate the city fleet structure in terms of the vehicles’ capacity was conducted for the Talas city (Kazakhstan) based on the proposed approach with use of the corresponding software implementation of the developed mathematical models. As a result of the experimental studies, the impact of the passengers’ flow structure and the number of carriers on the rational structure of the city bus fleet was studied in the paper.

Boosting reaction kinetics and improving long cycle life in lamellar VS2/MoS2 Heterojunctions for superior sodium storage performance

The development of high-performance rechargeable batteries highly depends on the rational structure/phase design of advanced electrode materials. A unique 2D lamellar stacked nanosheet VS2/MoS2 heterostructure is synthesized using a simple...

The model of the organizational and technical weapons and military equipment recovery system

Analysis of wars and armed conflicts in recent years and the performance of tasks by military units (subunits) in a United Forces operation (anti-terrorist operation) confirms that the success of the troops (forces) in performing tasks will depend on the performance of the logistics system. The availability of military units with serviceable weapons and military equipment (WME) ensures the fulfillment of the mission and the advantage over the enemy. At the same time, the timeliness of providing military units (subunits) with serviceable weapons and military equipment depends on the efficiency of the logistics system, namely, on the recovery subsystem, which is its component. However, as studies have shown, there is currently insufficient sufficiency of the recovery system. All this is related to the definition of the composition of forces and means and the structure of the WME recovery system at different levels of the hierarchy. Therefore, in the article, it is considered that for the WME recovery system, the main parameter is the allowable time of WME recovery, differentiated by levels of complexity of tasks. Determination of this parameter for the basic variant of construction of WME recovery system is proposed using the average indicator of the intensity of the flow of possible volumes of tasks on the WME recovery. To determine the rational structure of WME recovery system and to calculate its main parameters the combined method of optimization of WME recovery system was used. Containing two stages: on the first - based on the requirements to the permissible terms of WME recovery system, the rational structure of the recovery system is defined, and on the second – using the method of statistical modeling, the parameters of the structure and composition of forces and means of the WME recovery system at each level of the hierarchy are defined.

Laws of Motion of the Lower Extremities and Structural-parametric Synthesis of Electro-hydraulic Executive Modules of the Active Exoskeleton According to the Criterion of Energy Suffiency

The object of the research is the electro-hydraulic executive modules (drives) of the exoskeleton of the lower extremities with a rigid structure of the power frame. The problem of schematic and parametric execution of modules located in the linkage joints of the exoskeleton which is used for verticalization of patients is considered. The aim of the study is to estimates energy consumption, sensitivity, establish a rational structure and parameters of modules that provide programmed movement according to the criterion of energy sufficiency. The laws of motion and diagrams of loads required for lifting a patient from a sitting position are presented.

The Development of the Method of Radar Observation System Construction of the Airspace on the Basis of Genetic Algorithm

The methodological approaches to the use of genetic algorithm for the synthesis of the rational structure of the radar surveillance system are proposed in the paper. The structure of the radar surveillance system is presented in the form of an incidence matrix, which is used as a chromosome by the operators of the genetic algorithm. This matrix is used as a chromosome by the operators of the genetic algorithm. The elements of the incidence matrix that describe the relationships between the elements of the structure of the observation system are genes in the genetic algorithm. In each cycle of the genetic algorithm, a pair of chromosomes is paired, during which part of the genes are exchanged, which for the system under study means the appearance and disappearance of the corresponding connections between the elements. The calculation of the values of the efficiency of radar surveillance for each variant of the structure is proposed to be carried out using the ant colony optimization. The gain in the value of the conditional probability of correct detection with a fixed probability of false alarm is approximately 10% Keywords— genetic algorithm, artificial intelligence, optimization, route, radar surveillance system.

Elucidating the Dynamics and Selective Mechanistic Mode of Inhibition of a Novel Poly ADP-Ribose Polymerase-1 Inhibitor

: Poly ADP-ribose polymerase-1 (PARP-1), due to its role in DNA damage and repair, has been identified as a crucial therapeutic target to attenuate cancer development and progression. More so, selective inhibition has remained a focal point in PARP-1 targeting and has led to the development of numerous compounds, including the recently identified Cpd10n, a novel homoerythrina alkaloid derivative. To expound on the selective PARP-1 inhibition mechanisms by Cpd10n, we employed computational simulation methods in this study. Findings revealed that the inhibitor stabilized the characteristic motion of activated PARP-1 as evidenced by reductions in residual deviations and structural flexibility. Findings further revealed that Cpd10n was favorably bound at the active site PARP-1 as supported by the occurrence of strong hydrogen and halogen bonds based on complementarity. These were in addition to aromatic bonds with an enhanced ring to ring stability. Steady and high-affinity interactions between the fluorine atom of Cpd10n and Glu988 could potentiate the selective activity of the compound. Interaction analyses also revealed that inhibitor binding was strongly dependent on electrostatic effects over van der Waal contributions, which were relatively minimal. We believe findings from this study will further contribute to the rational structure-based design of highly selective PARP-1 inhibitors.

Achieving effective and selective CK1 inhibitors through structure modification

Casein kinase 1 (CK1) is an extensively expressed serine/threonine kinase family, with six highly conserved isoforms of human CK1. Due to its involvement in many biological processes, CK1 is a promising target for several pathological states, including circadian sleep disorder, neurodegenerative diseases, cancer and inflammation. However, due to the structural similarities between the six CK1 members, the design of CK1 inhibitors is intricate. So far, no effective CK1 inhibitors are reported to reach clinical trials; thus, approaches to obtaining both selective and effective CK1 inhibitors are in great demand. Here we analyze several CK1 inhibitors that provide successful experience for structure-based drug design and rational structure modification, which could provide references for further drug design.