Further Development of an Application Framework for Computational Chemistry (AFCC) Applied to New Drug Discovery

2014 ◽  
pp. 92-110
Author(s):  
J. Tindle ◽  
M. Gray ◽  
R.L. Warrender ◽  
K. Ginty ◽  
P.K.D. Dawson
Keyword(s):  
Drug Discovery ◽  
Computational Chemistry ◽  
Task Scheduling ◽  
Molecular Modelling ◽  
Computational Efficiency ◽  
System Performance ◽  
Three Dimensional ◽  
Application Framework ◽  
Further Development ◽  
Cluster Computer

This chapter describes the performance of a compute cluster applied to solve Three Dimensional (3D) molecular modelling problems. The primary goal of this work is to identify new potential drugs. The chapter focuses upon the following issues: computational chemistry, computational efficiency, task scheduling, and the analysis of system performance. The philosophy of design for an Application Framework for Computational Chemistry (AFCC) is described. Eighteen months after the release of the original chapter, the authors have examined a series of changes adopted which have led to improved system performance. Various experiments have been carried out to optimise the performance of a cluster computer, the results analysed, and the statistics produced are discussed in the chapter.

Application Framework for Computational Chemistry (AFCC) Applied to New Drug Discovery

2012 ◽  
Vol 4 (2) ◽  
pp. 46-62 ◽  
Author(s):  
J. Tindle ◽  
M. Gray ◽  
R. L. Warrender ◽  
K. Ginty ◽  
P. Dawson
Keyword(s):  
Drug Discovery ◽  
Computational Chemistry ◽  
Task Scheduling ◽  
Molecular Modelling ◽  
Computational Efficiency ◽  
System Performance ◽  
Three Dimensional ◽  
Application Framework ◽  
Cluster Computer ◽  
Modelling Problems

This paper describes the performance of a compute cluster applied to solve three dimensional (3D) molecular modelling problems. The primary goal of this work is to identify new potential drugs. The paper examines the following issues: computational chemistry, computational efficiency, task scheduling, and the analysis of system performance. The philosophy of design for an application framework for computational chemistry (AFCC) is described. Various experiments have been carried out to optimise the performance of a cluster computer, the results analysed and the statistics produced are discussed in the paper.

scholarly journals New Methods for the Synthesis of Spirocyclic Cephalosporin Analogues

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 6035
Author(s):  
Alan X. Zhao ◽  
Louise E. Horsfall ◽  
Alison N. Hulme
Keyword(s):  
Drug Discovery ◽  
Protein Interactions ◽  
Molecular Modelling ◽  
Three Dimensional ◽  
Spiro Compounds ◽  
Synthetic Methodology ◽  
New Methods ◽  
Michael Type Addition ◽  
Novel Method

Spiro compounds provide attractive targets in drug discovery due to their inherent three-dimensional structures, which enhance protein interactions, aid solubility and facilitate molecular modelling. However, synthetic methodology for the spiro-functionalisation of important classes of penicillin and cephalosporin β-lactam antibiotics is comparatively limited. We report a novel method for the generation of spiro-cephalosporin compounds through a Michael-type addition to the dihydrothiazine ring. Coupling of a range of catechols is achieved under mildly basic conditions (K2CO3, DMF), giving the stereoselective formation of spiro-cephalosporins (d.r. 14:1 to 8:1) in moderate to good yields (28−65%).

scholarly journals Advancing Drug Discovery for Neurological Disorders Using iPSC-Derived Neural Organoids

2021 ◽  
Vol 22 (5) ◽  
pp. 2659
Author(s):  
Gianluca Costamagna ◽  
Giacomo Pietro Comi ◽  
Stefania Corti
Keyword(s):  
Drug Discovery ◽  
Drug Screening ◽  
Neural Development ◽  
Neurological Disorders ◽  
Large Scale ◽  
Three Dimensional ◽  
Induced Pluripotent Stem Cell ◽  
Cellular Level ◽  
Complex Data ◽  
Complex Data Sets

In the last decade, different research groups in the academic setting have developed induced pluripotent stem cell-based protocols to generate three-dimensional, multicellular, neural organoids. Their use to model brain biology, early neural development, and human diseases has provided new insights into the pathophysiology of neuropsychiatric and neurological disorders, including microcephaly, autism, Parkinson’s disease, and Alzheimer’s disease. However, the adoption of organoid technology for large-scale drug screening in the industry has been hampered by challenges with reproducibility, scalability, and translatability to human disease. Potential technical solutions to expand their use in drug discovery pipelines include Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) to create isogenic models, single-cell RNA sequencing to characterize the model at a cellular level, and machine learning to analyze complex data sets. In addition, high-content imaging, automated liquid handling, and standardized assays represent other valuable tools toward this goal. Though several open issues still hamper the full implementation of the organoid technology outside academia, rapid progress in this field will help to prompt its translation toward large-scale drug screening for neurological disorders.

scholarly journals Human iPSC-Based Modeling of Central Nerve System Disorders for Drug Discovery

2021 ◽  
Vol 22 (3) ◽  
pp. 1203
Author(s):  
Lu Qian ◽  
Julia TCW
Keyword(s):  
Drug Discovery ◽  
Disease Modeling ◽  
Three Dimensional ◽  
Structural Complexity ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Central Nerve System ◽  
Human Ipscs ◽  
Nerve System

A high-throughput drug screen identifies potentially promising therapeutics for clinical trials. However, limitations that persist in current disease modeling with limited physiological relevancy of human patients skew drug responses, hamper translation of clinical efficacy, and contribute to high clinical attritions. The emergence of induced pluripotent stem cell (iPSC) technology revolutionizes the paradigm of drug discovery. In particular, iPSC-based three-dimensional (3D) tissue engineering that appears as a promising vehicle of in vitro disease modeling provides more sophisticated tissue architectures and micro-environmental cues than a traditional two-dimensional (2D) culture. Here we discuss 3D based organoids/spheroids that construct the advanced modeling with evolved structural complexity, which propels drug discovery by exhibiting more human specific and diverse pathologies that are not perceived in 2D or animal models. We will then focus on various central nerve system (CNS) disease modeling using human iPSCs, leading to uncovering disease pathogenesis that guides the development of therapeutic strategies. Finally, we will address new opportunities of iPSC-assisted drug discovery with multi-disciplinary approaches from bioengineering to Omics technology. Despite technological challenges, iPSC-derived cytoarchitectures through interactions of diverse cell types mimic patients’ CNS and serve as a platform for therapeutic development and personalized precision medicine.

scholarly journals A Novel In Vitro Approach for Simultaneous Evaluation of CYP3A4 Inhibition and Kinetic Aqueous Solubility

2014 ◽  
Vol 20 (2) ◽  
pp. 254-264 ◽  
Author(s):  
José Pérez ◽  
Caridad Díaz ◽  
Francisco Asensio ◽  
Alexandra Palafox ◽  
Olga Genilloud ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Physicochemical Properties ◽  
Safety Concern ◽  
Aqueous Solubility ◽  
Cyp3a4 Inhibition ◽  
Use Of Resources ◽  
Simultaneous Evaluation ◽  
New Chemical Entities ◽  
Further Development

In the early stages of the drug discovery process, evaluation of the drug metabolism and physicochemical properties of new chemical entities is crucial to prioritize those candidates displaying a better profile for further development. In terms of metabolism, drug–drug interactions mediated through CYP450 inhibition are a significant safety concern, and therefore the effect of new candidate drugs on CYP450 activity should be screened early. In the initial stages of drug discovery, when physicochemical properties such as aqueous solubility have not been optimized yet, there might be a large number of candidate compounds showing artificially low CYP450 inhibition, and consequently potential drug–drug interaction toxicity might be overlooked. In this work, we present a novel in vitro approach for simultaneous evaluation of CYP3A4 inhibition potential and kinetic aqueous solubility (NIVA-CYPI-KS). This new methodology is based on fluorogenic CYP450 activities and turbidimetric measurements for compound solubility, and it provides a significant improvement in the use of resources and a better understanding of CYP450 inhibition data.

2D X-ray diffraction and molecular modelling of the crystalline structure of polyesters under uniaxial stress

2021 ◽  
pp. 096739112199822
Author(s):  
Ahmed I Abou-Kandil ◽  
Gerhard Goldbeck
Keyword(s):  
Crystalline Structure ◽  
Molecular Modelling ◽  
Three Dimensional ◽  
Uniaxial Stress ◽  
X Ray Diffraction ◽  
X Ray ◽  
Wide Range ◽  
Modelling Techniques ◽  
Diffraction Patterns

Studying the crystalline structure of uniaxially and biaxially drawn polyesters is of great importance due to their wide range of applications. In this study, we shed some light on the behaviour of PET and PEN under uniaxial stress using experimental and molecular modelling techniques. Comparing experiment with modelling provides insights into polymer crystallisation with extended chains. Experimental x-ray diffraction patterns are reproduced by means of models of chains sliding along the c-axis leading to some loss of three-dimensional order, i.e. moving away from the condition of perfect register of the fully extended chains in triclinic crystals of both PET and PEN. This will help us understand the mechanism of polymer crystallisation under uniaxial stress and the appearance of mesophases in some cases as discussed herein.

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