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SSRN 2023年

作者： Singh, Vishal K. Ahmad, Iqrar Patel, Harun Chaurasia, Himani Organic Synthesis and Process Chemistry Division CSIR- Indian Institute of Chemical Technology Hyderabad500007 India Division of Computer Aided Drug Design Department of Pharmaceutical Chemistry H. R. Patel Institute of Pharmaceutical Education and Research Maharashtra Shirpur425405 India Department of Chemistry University of Allahabad Prayagraj211002 India

Herein, we report the design, antibacterial and antifungal evaluation of some quinoline derivatives. Molecular docking and molecular dynamics (MD) simulations were performed on molecule 2, 6 and sulfamethoxazole with peptide deformylase (PDF) protein (PDB ID: 1G2A). Comprehensive MD analysis revealed that compound 2 and 6 shows conformational stability, higher inhibitory action and a balance between flexibility and stability. Antibacterial screening was performed against different human pathogenic bacteria, viz. B. cerus, S. aureus, E. coli and P. aeruginosa. Further combinatorial antibacterial screening with reference drug were performed. The MIC data obtained from different methods of combination approach revealed that combined MIC of compounds were lowered by to of their original MIC. Antifungal screening were also performed, clearly indicated that compounds were also potentially active against several species of pathogenic fungal strains, viz. A. flavus, A. niger, F. oxysporum and C. albicans. © 2023, The Authors. All rights reserved.

关键词： Molecular modeling

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Discovery of highly potent and selective CRBN-recruiting EGFR^L858R/T790M degraders in vivo

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European Journal of Medicinal Chemistry 2022年 238卷 114509页

作者： Zhang, Wenjuan Li, Pengyun Sun, Shiyang Jia, Changkai Yang, Ning Zhuang, Xiaomei Zheng, Zhibing Li, Song Laboratory of Computer-Aided Drug Design & Discovery Beijing Institute of Pharmacology and Toxicology Beijing 100850 China Key Laboratory of Drug Metabolism and Pharmacokinetics Beijing Institute of Pharmacology and Toxicology Beijing 100850 China

Currently, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are widely used in the treatment of non-small cell lung cancer (NSCLC). However, the inevitable drug resistance and side effects are the current main obstacle, which motivating novel therapies. Proteolysis targeting chimera (PROTAC), a lately-developed technology to target proteins for degradation, has been utilized for drug development. Therefore, we designed, synthesized and evaluated a series of CRBN-recruiting EGFR degraders. Among them, 13a and 13b significantly inhibited NCI–H1975 cells proliferation with IC₅₀ values of 58.08 nM and 46.82 nM, respectively, whereas exhibited more than 100 μM against A549 or H1299 cells, whose selectivity was more than 1700-fold. 13a and 13b potently induced the EGFR^L858R/T790M degradation by ubiquitin proteasome system in a time- and dose-dependent manner but not that of EGFR^WT, and the DC₅₀ values of 13b was 13.2 nM, which was the most potent compound in current known CRBN-recruiting EGFR^L858R/T790M degraders. 13a and 13b dramatically induced cell apoptosis, cell cycle arrest and inhibited downstream signaling pathways. Furthermore, 13a and 13b effectively and selectively inhibited NCI–H1975 xenograft tumor growth with good pharmacokinetics (PK) properties in vivo. These findings demonstrate that 13a and 13b could serve as candidates for developing the drug for treating NSCLC. © 2022 Elsevier Masson SAS

关键词： Antitumor CADD EGFRL858R/T790M PK and PD PROTAC

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On the Minimization of Boolean Functions for Additive Complexity Measures

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Journal of Applied and Industrial Mathematics 2019年第3期13卷 418-435页

作者： Chukhrov, I.P. Institute of Computer Aided Design Vtoraya Brestskaya ul. 19/18 Moscow123056 Russia

The problem of minimizing Boolean functions for additive complexity measures in a geometric interpretation, as covering a subset of vertices in the unit cube by faces, is a special type of a combinatorial statement of the weighted problem of a minimal covering of a set. Its specificity is determined by the family of covering subsets, the faces of the unit cube, that are contained in the set of the unit vertices of the function, as well as by the complexity measure of the faces, which determines the weight of the faces when calculating the complexity of the covering. To measure the complexity, we need nonnegativity, monotonicity in the inclusion of faces, and equality for isomorphic faces. For additive complexity measures, we introduce a classification in accordance with the order of the growth of the complexity of the faces depending on the dimension of the cube and study the characteristics of the complexity of the minimization of almost all Boolean functions. © 2019, Pleiades Publishing, Ltd.

关键词： Boolean functions

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Optical and Electron Microscopy Studies of Al2O3Nanomatrices with Embedded ADP and KB5 Nanocrystals 12

Optical and Electron Microscopy Studies of Al2O3Nanomatrices...

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12th IEEE International Conference "Nanomaterials: Applications and Properties", NAP 2022

作者： Andrushchak, Nazariy Vynnyk, Dmytro Adamiv, Volodymyr Haiduchok, Volodymyr Strelchuk, Viktor Nikolenko, Andrii Zhydachevskyy, Yaroslav Shchur, Yaroslav Andrushchak, Anatoliy Lviv Polytechnic National University Computer-Aided Design Systems Lviv Ukraine Lviv Polytechnic National University Department Of Applied Physics And Nanomaterials Science Lviv Ukraine Vlokh Institute Of Physical Optics Department Of Optical Materials Lviv Ukraine Scientific Research Company 'Electron-Carat' Lviv Ukraine V.E. Lashkaryov Institute Of Semiconductor Physics National Academy Of Sciences Of Ukraine Kyiv Ukraine Institute Of Physics Polish Academy Of Sciences Warsaw Poland Institute For Condensed Matter Physics National Academy Of Sciences Of Ukraine Lviv Ukraine

ISBN: (数字)9781665489829

ISBN: (纸本)9781665489829

In this contribution, we report on the optical spectra of nanocomposite based on the Al2O3 nanoporous matrices with embedded ADP and KB5 nanocrystals. The reflection, absorption, and transmission spectra were recorded in the range of 1-50μm. The reflection coefficient of Al2O3 nanomatrices depends on the method of obtaining Al sheets, which are used for the manufacture of Al2O3 host matrices. For example, the value of the reflection coefficient of nanomatrices with embedded ADP crystals was 7-5.5%, whereas this coefficient for Al2O3 nanomatrices with KB5 crystals was smaller, 4.5-4.0%. The reflection spectra of the nanoporous matrices of Al2O3 with the embedded ADP crystals can be decreased to ∼1% in the range of 1-10μm which may be explained either as a result of high diffusion scattering or a low refractive index. In addition, the performed SEM analysis has indicated that Al2O3+ADP samples with the same pore diameter of 75 nm practically have similar percentages of the coverage area, while for Al2O3+KB5 samples, the coverage area is almost clean. © 2022 IEEE.

关键词： Refractive index

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Current strategies to address data scarcity in artificial intelligence-based drug discovery: A comprehensive review

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computers in Biology and Medicine 2024年 179卷 108734-108734页

作者： Gangwal, Amit Ansari, Azim Ahmad, Iqrar Azad, Abul Kalam Wan Sulaiman, Wan Mohd Azizi Department of Natural Product Chemistry Shri Vile Parle Kelavani Mandal's Institute of Pharmacy Maharashtra Dhule424001 India Computer Aided Drug Design Center Shri Vile Parle Kelavani Mandal's Institute of Pharmacy Maharashtra Dhule424001 India Department of Pharmaceutical Chemistry Prof. Ravindra Nikam College of Pharmacy Gondur Maharashtra Dhule424002 India Faculty of Pharmacy University College of MAIWP International Batu Caves Kuala Lumpur68100 Malaysia

Artificial intelligence (AI) has played a vital role in computer-aided drug design (CADD). This development has been further accelerated with the increasing use of machine learning (ML), mainly deep learning (DL), and computing hardware and software advancements. As a result, initial doubts about the application of AI in drug discovery have been dispelled, leading to significant benefits in medicinal chemistry. At the same time, it is crucial to recognize that AI is still in its infancy and faces a few limitations that need to be addressed to harness its full potential in drug discovery. Some notable limitations are insufficient, unlabeled, and non-uniform data, the resemblance of some AI-generated molecules with existing molecules, unavailability of inadequate benchmarks, intellectual property rights (IPRs) related hurdles in data sharing, poor understanding of biology, focus on proxy data and ligands, lack of holistic methods to represent input (molecular structures) to prevent pre-processing of input molecules (feature engineering), etc. The major component in AI infrastructure is input data, as most of the successes of AI-driven efforts to improve drug discovery depend on the quality and quantity of data, used to train and test AI algorithms, besides a few other factors. Additionally, data-gulping DL approaches, without sufficient data, may collapse to live up to their promise. Current literature suggests a few methods, to certain extent, effectively handle low data for better output from the AI models in the context of drug discovery. These are transferring learning (TL), active learning (AL), single or one-shot learning (OSL), multi-task learning (MTL), data augmentation (DA), data synthesis (DS), etc. One different method, which enables sharing of proprietary data on a common platform (without compromising data privacy) to train ML model, is federated learning (FL). In this review, we compare and discuss these methods, their recent applications, and limitatio

关键词： Molecules

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Mathematical modeling of the mixed region dynamics in a nonhomogeneous medium 19

Mathematical modeling of the mixed region dynamics in a nonh...

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19th International Multidisciplinary Scientific Geoconference, SGEM 2019

作者： Gushchin, Valentin Smirnova, Irina A. Institute for Computer Aided Design of RAS Moscow Russia

ISBN: (纸本)9786197408768

Study of wave motions fluid is one of the most important and complex problems of modern hydrodynamics. A mathematical model for dynamics of incompressible uniform viscous liquid stains in stratified medium is suggested. This model is described by the Navier-Stokes equations in the Boussinesq approximation. Stratification component of medium is saltiness. Bearing in mind that in such flows there are areas with large gradients of hydrodynamic parameters required methods should possess such properties as a high order of accuracy, minimum scheme dissipation and dispersion, as well as monotony. To solve the task, use the authors developed a method of splitting by physical factors, the method SMIF (Splitting on physical factors Method for Incompressible Fluid flows) possessing by the above-mentioned properties. Fore steps splitting scheme is considered. This paper will provide a brief description of the method SMIF. The test calculations and comparison with some theoretical, experimental data and calculations of other authors will be demonstrated. © SGEM 2019.

关键词： Navier Stokes equations

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Separation of two meteoroid fragments during the flight in the atmosphere

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AIP Conference Proceedings 2023年第1期2849卷

作者： Vladislav Lukashenko Fedor Maksimov Institute for Computer Aided Design of RAS 19/18 Second Brestskaya Street 123056 Moscow Russia

A problem of two bodies separating in the atmosphere during supersonic flight was studied using multigrid method of modeling dynamics. Two main configurations were taken into consideration. When two fragments were initially located on the line perpendicular to the direction of the flight, they separated from each other symmetrically and acquired the same absolute value of lateral velocity. When fragments were initially located one behind another with a certain distance between them, collimation effect was observed with the lagging fragment moving into the near wake area of the leading body. A series of consequential collisions of bodies occurred with the distance between fragments decreasing over time in the case of inelastic impact. Eventually the system transitioned to the state of the joint flight of two bodies one directly behind the other. Over time numerical disturbances lead to the break of symmetry with fragments sliding against each other and then separating in lateral direction. The separation velocity of the leading body was significantly higher for this configuration. The joint flight of two bodies behind each other was found to be unstable unless the lagging fragment had smaller size than leading body.

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Evolution of the Diffusion-Induced Flow over a Disk Submerged in a Stratified Viscous Fluid

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Mathematical Models and computer Simulations 2019年第3期11卷 479-487页

作者： Matyushin, P.V. Institute for Computer-Aided Design Russian Academy of Sciences Moscow Russian Federation

Abstract: The paper presents the results of the mathematically simulated evolution of a 3D diffusion-induced flow over a disk (with diameter d and thickness H = 0.76 d) immersed in a linearly density-stratified incompressible viscous fluid (described by a system of the Navier–Stokes equations in the Boussinesq approximation). The disk rests at the level of the neutral buoyancy (coinciding with its symmetry axis z) and disturbs the homogeneity of the background diffusion flux in the fluid forming a complex system of slow currents (internal gravitational waves). Over time, two thin horizontal convection cells are formed at the upper and lower parts of the disk stretching parallel to the z axis and adjacent to the base cell with thickness d/2. This work is the first to analyze in detail the fundamental mechanism for the formation of each new half-wave near the vertical axis x (passing through the center of the disk) during half the buoyancy period of the fluid T_b. This mechanism is based on gravitational instability. The emergence of this instability is first detected at 0.473T_b at a height of 3.9 d above the center of the disk. The same mechanism is also implemented over the place where the body moves in the horizontal direction. The 3D vortex structure of the flow is visualized by constructing the isosurfaces of the imaginary part of the complex-conjugate eigenvalues of the velocity gradient tensor. In mathematical simulation, we employed a numerical method SMIF that has proved itself over three decades with an explicit hybrid finite-difference scheme for the approximation of the convective terms of the equations (second-order approximation, monotonicity). © 2019, Pleiades Publishing, Ltd.

关键词： 3D vortex structure convective cell crest diffusion disk internal waves mathematical simulation stratified viscous fluid trough visualization

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Mathematical Simulation of the Fall and Fragmentation of the Sikhote-Alin Bolide

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Mathematical Models and computer Simulations 2019年第3期11卷 451-456页

作者： Andrushchenko, V.A. Syzranova, N.G. Institute for Computer-Aided Design Russian Academy of Sciences Moscow Russian Federation

Abstract: The problem of the hypersonic motion, destruction, and fragmentation of the Sikhote-Alin bolide in the atmosphere under the influence of power and thermal loads is studied numerically. Two mechanisms of heat transfer from the gas to the surface of the celestial body are taken into account: convective and radiative. The priority of each mechanism is studied on different parts of the trajectory of the fall. The process of the progressive fragmentation of the bolide is considered in the model of sequential fracturing. At the final stage of the fall, the process of small fragments breaking into dust due to temperature stresses is taken into account. It is noted that the results of the calculations reflect the actual process of fragmentation of the bolide qualitatively correctly. © 2019, Pleiades Publishing, Ltd.

关键词： bolide destruction fragmentation hypersonic motion mathematical simulation

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Modeling a Flow around Permeable Surfaces

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Mathematical Models and computer Simulations 2019年第4期11卷 531-541页

作者： Shevelev, Yu. D. Maksimov, F.A. Institute of Computer-Aided Design Russian Academy of Sciences Moscow Russian Federation

Abstract: The paper presents a method for calculating a flow around a permeable surface using a set of bodies modeling the impermeable part of the surface. The permeable surface is simulated by a finite relatively small number of elements determined by the available computer processing capabilities. The similarity between the aerodynamic properties of the surface in the mathematical model and the real surface is provided by the geometric similarity between the shape of the surface elements and the equal value of the permeability coefficient. Comparison of the calculation results with the experimental findings shows the possibility of a reasonably reliable prediction for the aerodynamic properties of permeable surfaces. An example is given of calculating the flow around tori with different geometric shapes, which shows that calculations can be carried out in a wide variation range of the permeability coefficient. Examples of calculating the flow around a permeable cone and cylinder are presented to demonstrate the possibility of modeling flows in the vicinity of complex configurations. A software package for modeling two-dimensional plane and axisymmetric flows near permeable surfaces is implemented. © 2019, Pleiades Publishing, Ltd.

关键词： aerodynamic properties numeric modeling permeable surface

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