Many medicinal chemistry relevant structures and core scaffolds tend towards geometric planarity. However, structural planarity may preclude the optimisation of physicochemical properties desirable in drug-like molecules, such as solubility. Furthermore, as new and challenging drug targets, such as protein-protein interactions, become more prevalent in drug design projects, the inherent potential to exploit three-dimensionality of chemical structures in lead optimisation is increasingly important. To this end, there has been recent interest in designing molecular fragments for fragment screening and subsequent derivatisation that exhibit enhanced three-dimensionality [1]. However, it remains unclear the extent to which core scaffolds require enhanced three-dimensionality in order to yield molecular designs with desired three-dimensionality.
Here, three computational methods are applied to investigate the emergence of three-dimensionality in drug-like molecules, namely: fragmentation analysis using a recently reported fragmentation algorithm, SynDiR [2]; iterative pruning of pendant substituents using the Scaffold Tree fragmentation rules [3,4]; and the virtual enumeration of drug-like molecules from molecular fragments of varying three-dimensionality. Using the recently published three-dimensionality descriptor Plane of Best Fit (PBF), amongst other descriptors, it is possible to assess the potential three-dimensionality of molecular fragments objectively [5]. The combination of these three approaches to investigate the emergence of three-dimensionality in drug-like molecules informs on the stages at which three-dimensionality should be considered in a drug design project. These methods permit a greater understanding of the properties of the derived functional groups and scaffolds from exemplified medicinal chemistry space and their contributions to three- dimensionality. This study has highlighted key learning that is anticipated to enhance medicinal chemistry design in the future.
Presentation made at PepTalk 2011 in San Diego on Jan. 13, 2011. The emphasis is on computational methods to explore global and local structure similarities in determining the possible promiscuity of drugs to bind to multiple protein receptors.
Presentation made at PepTalk 2011 in San Diego on Jan. 13, 2011. The emphasis is on computational methods to explore global and local structure similarities in determining the possible promiscuity of drugs to bind to multiple protein receptors.
Mike generously is sharing this slide set which he presented at the 250th meeting of the ACS 2015 so that others who think they can not afford to run drug discovery can consider this economical distributed, virtual model….and to see CDD Vault in action.
Talk delivered at Warwick Biomedical Engineering Seminar series 27 November 2014. Develops a theme emerging from a review in 2010:
J Watkins, A Marsh, P C Taylor, D R J Singer
Therapeutic Delivery, 2010, 1, 651-665
"Continued adherence to a single-drug single-target paradigm will limit the ability of chemists to contribute to advances in personalized medicine, whether they be in discovery or delivery"
The culture of cells in two dimensions does not reproduce the histological characteristics of a tissue for informative or useful study. Growing cells as three-dimensional (3D) models more analogous to their existence in vivo may be more clinically relevant. Discuss the potential of using three dimensional cell cultures for anti-cancer drug screening.
A physical sciences network characterization of non-tumorigenic and metastati...Shashaanka Ashili
To investigate the transition from non-cancerous to metastatic from a physical sciences perspective, the
Physical Sciences–Oncology Centers (PS-OC) Network performed molecular and biophysical comparative studies of the non-tumorigenic MCF-10A and metastatic DA-MB-231 breast epithelial cell lines, commonly used as models of cancer metastasis. Experiments were performed in 20 laboratories from 12 PS-OCs. Each laboratory was supplied with identical aliquots and common reagents and culture protocols. Analyses of these measurements revealed dramatic differences in their mechanics, migration, adhesion, oxygen response, and proteomic profiles. Model-based multi-omics approaches identified key differences between these cells’ regulatory networks involved in morphology and survival. These results provide a multifaceted description of cellular parameters of two widely used cell lines and demonstrate the value of the PS-OC Network approach for integration of diverse experimental observations to elucidate the phenotypes associated with cancer metastasis.
Ensuring Chemical Structure, Biological Data and Computational Model Quality
A talk given at SLAS 2016 mon Jan 25th in San Diego
covers published work and recent forays with BIA 10-2474
Toxic effects of heavy metals : Lead and Arsenicsanjana502982
Heavy metals are naturally occuring metallic chemical elements that have relatively high density, and are toxic at even low concentrations. All toxic metals are termed as heavy metals irrespective of their atomic mass and density, eg. arsenic, lead, mercury, cadmium, thallium, chromium, etc.
Mike generously is sharing this slide set which he presented at the 250th meeting of the ACS 2015 so that others who think they can not afford to run drug discovery can consider this economical distributed, virtual model….and to see CDD Vault in action.
Talk delivered at Warwick Biomedical Engineering Seminar series 27 November 2014. Develops a theme emerging from a review in 2010:
J Watkins, A Marsh, P C Taylor, D R J Singer
Therapeutic Delivery, 2010, 1, 651-665
"Continued adherence to a single-drug single-target paradigm will limit the ability of chemists to contribute to advances in personalized medicine, whether they be in discovery or delivery"
The culture of cells in two dimensions does not reproduce the histological characteristics of a tissue for informative or useful study. Growing cells as three-dimensional (3D) models more analogous to their existence in vivo may be more clinically relevant. Discuss the potential of using three dimensional cell cultures for anti-cancer drug screening.
A physical sciences network characterization of non-tumorigenic and metastati...Shashaanka Ashili
To investigate the transition from non-cancerous to metastatic from a physical sciences perspective, the
Physical Sciences–Oncology Centers (PS-OC) Network performed molecular and biophysical comparative studies of the non-tumorigenic MCF-10A and metastatic DA-MB-231 breast epithelial cell lines, commonly used as models of cancer metastasis. Experiments were performed in 20 laboratories from 12 PS-OCs. Each laboratory was supplied with identical aliquots and common reagents and culture protocols. Analyses of these measurements revealed dramatic differences in their mechanics, migration, adhesion, oxygen response, and proteomic profiles. Model-based multi-omics approaches identified key differences between these cells’ regulatory networks involved in morphology and survival. These results provide a multifaceted description of cellular parameters of two widely used cell lines and demonstrate the value of the PS-OC Network approach for integration of diverse experimental observations to elucidate the phenotypes associated with cancer metastasis.
Ensuring Chemical Structure, Biological Data and Computational Model Quality
A talk given at SLAS 2016 mon Jan 25th in San Diego
covers published work and recent forays with BIA 10-2474
Toxic effects of heavy metals : Lead and Arsenicsanjana502982
Heavy metals are naturally occuring metallic chemical elements that have relatively high density, and are toxic at even low concentrations. All toxic metals are termed as heavy metals irrespective of their atomic mass and density, eg. arsenic, lead, mercury, cadmium, thallium, chromium, etc.
Nutraceutical market, scope and growth: Herbal drug technologyLokesh Patil
As consumer awareness of health and wellness rises, the nutraceutical market—which includes goods like functional meals, drinks, and dietary supplements that provide health advantages beyond basic nutrition—is growing significantly. As healthcare expenses rise, the population ages, and people want natural and preventative health solutions more and more, this industry is increasing quickly. Further driving market expansion are product formulation innovations and the use of cutting-edge technology for customized nutrition. With its worldwide reach, the nutraceutical industry is expected to keep growing and provide significant chances for research and investment in a number of categories, including vitamins, minerals, probiotics, and herbal supplements.
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...Sérgio Sacani
Since volcanic activity was first discovered on Io from Voyager images in 1979, changes
on Io’s surface have been monitored from both spacecraft and ground-based telescopes.
Here, we present the highest spatial resolution images of Io ever obtained from a groundbased telescope. These images, acquired by the SHARK-VIS instrument on the Large
Binocular Telescope, show evidence of a major resurfacing event on Io’s trailing hemisphere. When compared to the most recent spacecraft images, the SHARK-VIS images
show that a plume deposit from a powerful eruption at Pillan Patera has covered part
of the long-lived Pele plume deposit. Although this type of resurfacing event may be common on Io, few have been detected due to the rarity of spacecraft visits and the previously low spatial resolution available from Earth-based telescopes. The SHARK-VIS instrument ushers in a new era of high resolution imaging of Io’s surface using adaptive
optics at visible wavelengths.
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
Monitor common gases, weather parameters, particulates.
Slide 1: Title Slide
Extrachromosomal Inheritance
Slide 2: Introduction to Extrachromosomal Inheritance
Definition: Extrachromosomal inheritance refers to the transmission of genetic material that is not found within the nucleus.
Key Components: Involves genes located in mitochondria, chloroplasts, and plasmids.
Slide 3: Mitochondrial Inheritance
Mitochondria: Organelles responsible for energy production.
Mitochondrial DNA (mtDNA): Circular DNA molecule found in mitochondria.
Inheritance Pattern: Maternally inherited, meaning it is passed from mothers to all their offspring.
Diseases: Examples include Leber’s hereditary optic neuropathy (LHON) and mitochondrial myopathy.
Slide 4: Chloroplast Inheritance
Chloroplasts: Organelles responsible for photosynthesis in plants.
Chloroplast DNA (cpDNA): Circular DNA molecule found in chloroplasts.
Inheritance Pattern: Often maternally inherited in most plants, but can vary in some species.
Examples: Variegation in plants, where leaf color patterns are determined by chloroplast DNA.
Slide 5: Plasmid Inheritance
Plasmids: Small, circular DNA molecules found in bacteria and some eukaryotes.
Features: Can carry antibiotic resistance genes and can be transferred between cells through processes like conjugation.
Significance: Important in biotechnology for gene cloning and genetic engineering.
Slide 6: Mechanisms of Extrachromosomal Inheritance
Non-Mendelian Patterns: Do not follow Mendel’s laws of inheritance.
Cytoplasmic Segregation: During cell division, organelles like mitochondria and chloroplasts are randomly distributed to daughter cells.
Heteroplasmy: Presence of more than one type of organellar genome within a cell, leading to variation in expression.
Slide 7: Examples of Extrachromosomal Inheritance
Four O’clock Plant (Mirabilis jalapa): Shows variegated leaves due to different cpDNA in leaf cells.
Petite Mutants in Yeast: Result from mutations in mitochondrial DNA affecting respiration.
Slide 8: Importance of Extrachromosomal Inheritance
Evolution: Provides insight into the evolution of eukaryotic cells.
Medicine: Understanding mitochondrial inheritance helps in diagnosing and treating mitochondrial diseases.
Agriculture: Chloroplast inheritance can be used in plant breeding and genetic modification.
Slide 9: Recent Research and Advances
Gene Editing: Techniques like CRISPR-Cas9 are being used to edit mitochondrial and chloroplast DNA.
Therapies: Development of mitochondrial replacement therapy (MRT) for preventing mitochondrial diseases.
Slide 10: Conclusion
Summary: Extrachromosomal inheritance involves the transmission of genetic material outside the nucleus and plays a crucial role in genetics, medicine, and biotechnology.
Future Directions: Continued research and technological advancements hold promise for new treatments and applications.
Slide 11: Questions and Discussion
Invite Audience: Open the floor for any questions or further discussion on the topic.
The ability to recreate computational results with minimal effort and actionable metrics provides a solid foundation for scientific research and software development. When people can replicate an analysis at the touch of a button using open-source software, open data, and methods to assess and compare proposals, it significantly eases verification of results, engagement with a diverse range of contributors, and progress. However, we have yet to fully achieve this; there are still many sociotechnical frictions.
Inspired by David Donoho's vision, this talk aims to revisit the three crucial pillars of frictionless reproducibility (data sharing, code sharing, and competitive challenges) with the perspective of deep software variability.
Our observation is that multiple layers — hardware, operating systems, third-party libraries, software versions, input data, compile-time options, and parameters — are subject to variability that exacerbates frictions but is also essential for achieving robust, generalizable results and fostering innovation. I will first review the literature, providing evidence of how the complex variability interactions across these layers affect qualitative and quantitative software properties, thereby complicating the reproduction and replication of scientific studies in various fields.
I will then present some software engineering and AI techniques that can support the strategic exploration of variability spaces. These include the use of abstractions and models (e.g., feature models), sampling strategies (e.g., uniform, random), cost-effective measurements (e.g., incremental build of software configurations), and dimensionality reduction methods (e.g., transfer learning, feature selection, software debloating).
I will finally argue that deep variability is both the problem and solution of frictionless reproducibility, calling the software science community to develop new methods and tools to manage variability and foster reproducibility in software systems.
Exposé invité Journées Nationales du GDR GPL 2024
What is greenhouse gasses and how many gasses are there to affect the Earth.moosaasad1975
What are greenhouse gasses how they affect the earth and its environment what is the future of the environment and earth how the weather and the climate effects.
THE IMPORTANCE OF MARTIAN ATMOSPHERE SAMPLE RETURN.Sérgio Sacani
The return of a sample of near-surface atmosphere from Mars would facilitate answers to several first-order science questions surrounding the formation and evolution of the planet. One of the important aspects of terrestrial planet formation in general is the role that primary atmospheres played in influencing the chemistry and structure of the planets and their antecedents. Studies of the martian atmosphere can be used to investigate the role of a primary atmosphere in its history. Atmosphere samples would also inform our understanding of the near-surface chemistry of the planet, and ultimately the prospects for life. High-precision isotopic analyses of constituent gases are needed to address these questions, requiring that the analyses are made on returned samples rather than in situ.
PRESENTATION ABOUT PRINCIPLE OF COSMATIC EVALUATION
On the origins of three-dimensionality in drug-like molecules
1. in partnership with
Making the discoveries that defeat cancer
On the Origins of Three-
Dimensionality in Drug-Like
Molecules
Dr Nathan Brown
Group Leader, In Silico Medicinal Chemistry
Cancer Research UK Cancer Therapeutics Unit
Division of Cancer Therapeutics
The Institute of Cancer Research, London
Chemical Computing Group Conference, Vienna, Austria, 2016
Thursday 19th May, 2016 @nathanbroon
2. Overview 2
• Motivations for enhanced three-dimensionality
• Descriptors of three-dimensionality
• PMI: Principal Moments of Inertia
• PBF: Plane of Best Fit
• Three-dimensionality analyses of drug-like space
• Extant drug-like molecules
• ‘Retrosynthetic’ analyses
• Fragmentation analyses
• Virtual libraries
3. Structural Moieties Promoting 3D 3
Quaternary
Centres
Bridged
Bicycles
Conformational
Restriction
Spiro Ring
Systems
Effexor XR
(Venlafaxine)
$1,431 Million (19th)
ANTIDEPRESS. & MOOD STAB.
Avapro
(Irbesartan)
$370 Million (91st)
ANGIOTEN-II ANTAG, PLAIN
Spiriva
(Tiotropium)
$1,594 Million (14th)
ANTICHOLINERGIC+B2-STIM
Zetia
(Ezetimibe)
$986 Million (31st)
CHOLEST.&TRIGLY. REGULATOR
28/12/1993
30/01/2004
30/09/1997
25/10/2002
4. Motivation: Three-Dimensional Molecules
• Mimicking natural products
• Natural products frequently incorporate 3D
scaffolds
• Improvement in properties
• 3D shape often conveys improved aqueous
solubility
• Addressing new and challenging drug targets
• e.g. protein-protein interactions
4
PDB: 3MXF
(+)-JQ1
5. Escape from Flatland… 5
1. Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52, 6752-6756.
6. PMI: Principal Moments of Inertia 6
NPR1
NPR20.51
0 0.5 1
disc
rod sphere
ChEMBL Drug-Like Small Molecules
Intuitive in Presentation
Size Independent
1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.
7. PBF: Plane of Best Fit 7
ChEMBL Drug-Like Molecules
0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
2.00
PlaneofBestFitSimple in Concept
Size Dependency
Unbound Descriptor
1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.
2. Firth, N. C.; Brown, N.; Blagg, J. Plane of Best Fit: A Novel Method to Characterize the Three-Dimensionality of Molecules. J. Chem. Inf. Model. 2012, 52, 2516-
2525.
8. Plane of Best Fit 8
0Å 1Å
0.16Å
0.27Å 0.64Å
0.80Å
1.06Å
0.40Å
1. Firth, N. C.; Brown, N.; Blagg, J. Plane of Best Fit: A Novel Method to Characterize the Three-Dimensionality of Molecules. J. Chem. Inf. Model. 2012, 52, 2516-
2525.
9. 9
PMI & PBF – Perfect Partners
1. Firth, N. C.; Brown, N.; Blagg, J. Plane of Best Fit: A Novel Method to Characterize the Three-Dimensionality of Molecules. J. Chem. Inf. Model. 2012, 52, 2516-
2525.
10. Scaffold Tree Fragmentation 10
Parent Level 3 Level 2 Level 1 2 Level 0
Simple & Intuitive Rules
Mimics Chemist Thinking
Systematic Evaluation
1. Schuffenhauer, A.; Ertl, P.; Roggo, S.; Wetzel, S.; Koch, M. A.; Waldmann, H. The Scaffold Tree – Visualization of the Scaffold Universe by Hierarchical
Classification. J. Chem. Inf. Model. 2007, 47, 47-58.
2. Langdon, S. R.; Brown, N.; Blagg, J. Scaffold Diversity of Exemplified Medicinal Chemistry Space. J. Chem. Inf. Model. 2012, 51, 2174-2185.
11. PMI: Scaffold Tree Analysis of ChEMBL
Return to Flatland…
11
Level 5 Level 4 Level 3
Level 2 Level 1 Level 0
Medicinal Chemistry Relevant Scaffolds Tend Towards Planarity
1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.
12. PBF: Scaffold Tree Analysis of ChEMBL
Return to Flatland…
12
1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.
Parents 8 7 6 5 4 3 2 1 0
Scaffold Tree Levels
0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
2.00
PlaneofBestFit
Medicinal Chemistry Relevant Scaffolds Tend Towards Planarity
13. Scaffolds versus ChEMBL Parents 13
A B C D E F G H
Increasing PBF
★ Core scaffold
Parent molecules
1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.
14. Scaffolds versus ChEMBL Parents 14
A
H
★ Core scaffold
Parent molecules
1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.
Modulation of Three-Dimensionality Easier with Planar Scaffolds
15. Scaffold versus ChEMBL Parent Molecules 15
A B C D E F G H
Increasing PBF
Fig 4 PBF distribution from all eight cores in one plot
A B C D E F G H
0.00
0.25
0.50
0.75
1.00
1.25
1.50
PlaneofBestFit
Fig 6 PBF distribution from all eight cores in one plot
More Three-Dimensional
Scaffolds Do Not
Necessarily Translate into
More Three-Dimensional
Structures
1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.
16. SynDiR – Synthetic Disconnection Rules 16
• New retrosynthetic fragmentation scheme published in 2015
1. Firth, N. C.; Atrash, B.; Brown, N.; Blagg, J. MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological
Evaluation. J. Chem. Inf. Model. 2015, 55, 1169-1180.
Most Substructures Tend Towards Planarity
Three-Dimensionality may Originate from Planar Moieties
Actual
Occurrence
Unique
Occurrence
17. SynDiR – Synthetic Disconnection Rules 17
Most Substructures Tend Towards Planarity
Three-Dimensionality may Originate from Planar Moieties
1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.
18. Scaffold versus Enumerated Libraries 18
A B C D E F G H
Increasing PBF
★ Core scaffold
Enumerated library
1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.
Medicinal Chemistry Relevant Scaffolds Tend Towards Planarity
19. Scaffold versus Enumerated Libraries 19
A B C D E F G H
Increasing PBFA B C D E F G H
0.00
0.25
0.50
0.75
1.00
1.25
1.50
PlaneofBestFit
Fig 6 PBF distribution from all eight cores in one plot
A B C D E F G H
0.00
0.25
0.50
0.75
1.00
1.25
1.50
PlaneofBestFit
Greater Increase in Three-
Dimensionality when
Starting from Flatter
Scaffolds…
…but final structures are
more 3D!
1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.
20. Summary & Conclusions
Presented approaches to analysing three-dimensionality
• Exemplified medicinal chemistry space
• Paring back structures to scaffolds
• Fragmenting into constituent substructures
• Enumerating virtual libraries
When and where can we enrich three-dimensionality?
• Constituent substructures are relatively planar
• Our medicinal chemistry scaffolds are typically flat
• Three-dimensionality can be modulated in design
• We do not need inherent three-dimensionality in scaffolds & groups
20
22. Acknowledgements 22
Cancer Research UK Grant No. C309/A8274
In Silico Medicinal Chemistry
• Fabio Broccatelli
• Michael Carter
• Nick Firth
• Teresa Kaserer
• Sarah Langdon
• Josh Meyers
• Yi Mok
• Lewis Vidler
Medicinal Chemistry
• Julian Blagg