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3D QSAR and pharmacophore studies on inhibitors of insuline like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) as potential anti-cancer agents

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Current research in Chemical Biology 2022年 2卷

作者： Mustafa Kamal Pasha Ishrat Jabeen Sandhya Samarasinghe Research Center for Modeling and Simulation National University of Sciences and Technology Islamabad Pakistan Complex Systems Big Data and Informatics Initiative (CSBII) Lincoln University New Zealand

Insulin like growth factor receptor (IGF-1R) and Insulin receptor (IR) are widely accepted to play a prominent role in cancer drug discovery due to their well-established involvement in various stages of tumorigenesis. Previously, neutralization of IGF-1R via monoclonal antibodies was in focus, which failed because of compensatory activation of IR-A upon inhibition of IGF-1R. Recent studies have demonstrated high homology between IGF-IR and IR particularly in tyrosine kinase domain and targeting both receptors have produced efficient therapeutic approaches such as inhibition of cancer cell cycle proliferation. Herein, we have made an attempt to analyze the unique data set from different chemical classes, containing potent ATP competitors against tyrosine kinase domain. We performed the 2D, 3D quantitative structure–activity relationship (QSAR) studies on inhibitors of these receptors to predict useful pharmacophoric features. We have optimized virtual screening of structurally diverse data set of dual inhibitors of IGF-1R and IR. Based on QSAR studies, we predict potential novel clinical candidates with a demonstrated absorption, distribution, metabolism, elimination, and toxicology (ADMETox) track. We also demonstrated comprehensive analysis of co–crystal complexes along with their inhibitors and built 3D- GRid INdependent Descriptors (GRIND) model to obtain insightful features such as H-bond donors and acceptors, overall topology and Vander Waal volume (vdw_vol) which are found to be responsible for dual inhibition of receptors. These findings lead to further description that Tirofiban, Practolol, Edoxaban, Novobiocin have potential to perform dual inhibition of both targets.

关键词： IGF1R IR Dual inhibitors Tyrosine kinase domain Small molecule inhibitors GRIND QSAR Pharmacophore

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Applying causal inference to understand emergent behavior 08

Applying causal inference to understand emergent behavior

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simulation Winter Conference

作者： Ross Gore Paul F. Reynolds Modeling and Simulation Technology Research Initiative Department of Computer Science University of Virginia Charlottesville VA USA

ISBN: (纸本)9781424427086

Emergent behaviors in simulations require explanation, so that valid behaviors can be separated from design or coding errors. Validation of emergent behavior requires accumulation of insight into the behavior and the conditions under which it arises. Previously, we have introduced an approach, Explanation Exploration (EE), to gather insight into emergent behaviors using semi-automatic model adaptation. We improve our previous work by iteratively applying causal inference procedures to samples gathered from the semi-automatic model adaptation. Iterative application of causal inference procedures reveals the interactions of identified abstractions within the model that cause the emergent behavior. Uncovering these interactions gives the subject matter expert new insight into the emergent behavior and facilitates the validation process.

关键词： Debugging Computational modeling Testing Probability distribution Adaptation model research initiatives Computer science Computer simulation Computer errors Process control

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An exploration-based taxonomy for emergent behavior analysis in simulations

An exploration-based taxonomy for emergent behavior analysis...

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2007 Winter simulation Conference, WSC

作者： Gore, Ross Reynolds Jr., Paul F. Modeling and Simulation Technology Research Initiative Department of Computer Science University of Virginia 151 Engineer's Way P.O. Box 400740 Charlottesville VA 22904-4740 United States

ISBN: (纸本)1424413060

Emergent behaviors in simulations require explanation, so that valid behaviors can be separated from design or coding errors. We present a taxonomy, to be applied to emergent behaviors of unknown validity. Our goal is to facilitate the explanation process. Once a user identifies an emergent behavior as a certain type within our taxonomy, exploration can commence in a manner befitting that type. Exploration based on type supports narrowing of possibilities and suggests exploration methods, thus facilitating the exploration process. Ideally, a taxonomy would be robust, allowing reasonable variation in behavior type assignment without penalty in cost or correctness during the exploration process. The taxonomy we present is robust, comprehensive and suitable for use with our established emergent behavior exploration methods. In addition to the taxonomy, we present our design rationale, and a summary of results from a test application of our taxonomy. © 2007 IEEE.

关键词： Taxonomies

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Requirements for DDDAS Flexible Point Support 06

Requirements for DDDAS Flexible Point Support

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simulation Winter Conference

作者： Joseph C. Carnahan Paul F. Reynolds Modeling and Simulation Technology Research Initiative Department of Computer Science University of Virginia Charlottesville VA USA

ISBN: (纸本)9781424405015

Dynamic data-driven application systems (DDDAS) integrate computer simulations with experimental observations to study phenomena with greater speed and accuracy than could be achieved by either experimentation or simulation alone. One of the key challenges behind DDDAS is automatically adapting simulations when experimental data indicates that a simulation must change. Coercion is a semi-automated simulation adaptation approach that can be automated further if elements of the simulation called flexible points are described in advance. In this paper, we use a number of DDDAS adaptation examples to identify the information that needs to be captured about flexible points in order to support coercion

关键词： Computational modeling Computer simulation Application software Context modeling research initiatives Computer science Performance gain Software performance Software design Analytical models

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Grand Challenge Case Studies in a simulation Curriculum 06

Grand Challenge Case Studies in a Simulation Curriculum

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simulation Winter Conference

作者： Michael Spiegel Paul F. Reynolds David C. Brogan Department of Computer Science Modeling and Simulation Technology Research Initiative University of Virginia Charlottesville VA USA

ISBN: (纸本)9781424405015

Students wishing to become experts in modeling and simulation (M&S) need to appreciate limitations of the technology. Our goal is to expose students to the current boundaries of simulation technology. To achieve this, we propose the incorporation of grand challenge case studies into a modeling and simulation curriculum. Grand challenge problems are defined as problems for which there does not exist a universally accepted solution (at present). We argue that grand challenge case studies are an excellent vehicle for discovering and appreciating current boundaries of M&S technology. We present three candidate case studies, one in detail - the ongoing U.S. Department of Energy analysis of Yucca Mountain as a location for nuclear waste storage with supporting discussion about how these cases can enhance exploration of the challenges in M&S technology. We discuss the proposed Yucca Mountain storage facility, along with two other case studies, and examine their integration into M&S curricula

关键词： Biological system modeling Spatial resolution Computational modeling Energy resolution Vehicles Radioactive pollution Energy storage Weather forecasting Diseases Corrosion

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The computational complexity of component selection in simulation reuse 05

The computational complexity of component selection in simul...

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simulation Winter Conference

作者： R.G. Bartholet D.C. Brogan P.F. Reynolds Modeling and Simulation Technology Research Initiative Department of Computer Science University of Virginia Charlottesville VA USA

ISBN: (纸本)9780780395190

simulation composability has been much more difficult to realize than some initially imagined. We believe that success lies in explicit considerations for the adaptability of components. In this paper, we show that the complexity of optimal component selection for adaptable components is NP-complete. However, our approach allows for the efficient adaptation of components to construct a complex simulation in the most flexible manner while allowing the greatest opportunity to meet all requirements, all the while reducing time and costs. We demonstrate that complexity can vary from polynomial, to NP, and even to exponential as a function of seemingly simple decisions made about the nature of dependencies among components. We generalize these results to show that regardless of the types or reasons for dependencies in component selection, just their mere existence makes this problem very difficult to solve optimally.

关键词： Computational complexity Computational modeling Software engineering Polynomials Computer simulation research initiatives Computer science Cost function Buildings Real time systems

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simulation-specific characteristics and software reuse 05

Simulation-specific characteristics and software reuse

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simulation Winter Conference

作者： J.C. Carnahan P.F. Reynolds D.C. Brogan Modeling and Simulation Technology Research Initiative Department of Computer Science University of Virginia Charlottesville VA USA

ISBN: (纸本)9780780395190

We argue that simulations possess interesting characteristics that facilitate adaptation. Simplifying assumptions, stochastic sampling, and event generation are common features which lend themselves to adaptation for reuse. In this paper, we explore simulation-specific characteristics amenable to adaptation and the ways they can be exploited in support of reuse. Our work is of particular relevance to research in component based simulations and dynamic data driven application systems, where adaptability and reuse are essential.

关键词： Object oriented modeling Computational modeling Software engineering Object oriented programming Stochastic processes Sampling methods Software design Computer simulation research initiatives Computer science

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A case study of model context for simulation composability and reusability 05

A case study of model context for simulation composability a...

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simulation Winter Conference

作者： M. Spiegel P.F. Reynolds D.C. Brogan Modeling and Simulation Technology Research Initiative Department of Computer Science University of Virginia Charlottesville VA USA

ISBN: (纸本)9780780395190

How much effort will be required to compose or reuse simulations? What factors need to be considered? It is generally known that composability and reusability are daunting challenges for both simulations and more broadly software design as a whole. We have conducted a small case study in order to clarify the role that model context plays in simulation composability and reusability. For a simple problem: compute the position and velocity of a falling body, we found that a reasonable formulation of a solution included a surprising number of implicit constraints. Equally surprising, in a challenge posed to a small group of capable individuals, no one of them was able to identify more than three-quarters of the ultimate set of validation constraints. We document the challenge, interpret its results, and discuss the utility our study will have in future investigations into simulation composition and reuse.

关键词： Context modeling Computer aided software engineering Computational modeling Software design Humans Gain measurement Gravity research initiatives Computer science Best practices

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