In this slide I covered the detailed about hansch analysis, Free-Wilson analysis, and Mixed approach. I also gave a detailed application for each points.
PHARMACOHORE MAPPING AND VIRTUAL SCRRENING FOR RESEARCH DEPARTMENTShikha Popali
THE PHARMACOPHORE MAPPING AND VIRTUAL SCRRENING , THESE PRESENTATION INCLUDES THE DEATIL ACCOUNT ON PHARMACOPHORE, MAPPING, ITS IDENTIFIATION FEATURES, ITS CONFORMATIONAL SEARCH, INSILICO DRUG DESIGN, VIRTUAL SCREENING, PHARMACOPHORE BASED SCREENING
What is QSAR?, introduction to 3D QSAR, CoMFA, CoMSIA, Case Study on CoMFA contour maps analysis and CoMSIA interactive forces between ligand and receptor, various Statistical techniques involved in QSAR
In this slide I covered the detailed about hansch analysis, Free-Wilson analysis, and Mixed approach. I also gave a detailed application for each points.
PHARMACOHORE MAPPING AND VIRTUAL SCRRENING FOR RESEARCH DEPARTMENTShikha Popali
THE PHARMACOPHORE MAPPING AND VIRTUAL SCRRENING , THESE PRESENTATION INCLUDES THE DEATIL ACCOUNT ON PHARMACOPHORE, MAPPING, ITS IDENTIFIATION FEATURES, ITS CONFORMATIONAL SEARCH, INSILICO DRUG DESIGN, VIRTUAL SCREENING, PHARMACOPHORE BASED SCREENING
What is QSAR?, introduction to 3D QSAR, CoMFA, CoMSIA, Case Study on CoMFA contour maps analysis and CoMSIA interactive forces between ligand and receptor, various Statistical techniques involved in QSAR
THE PRODRUG DESIGNING FOR NEW SELECTION AND FORMULATION OF DRUG COMPATIBLE WITH API I.E. ACTIVE PHARMACUTICAL INGREDIENT, AND ITS EFFECT WHICH SHOULD BE 0. THE DRUG COMBINED WITH API AND AVILABLE IN MARKET AND DRUGS NEED TO BE COMBINE ARE ALSO DISCUSSED WITH ITS STRUCTURE AND SAR, AND COVERED AS PER THE SYLLABUS OF PCI.
Analog design is usually defined as the modification of a drug molecule or of any bioactive compound in order to prepare a new molecule showing chemical and biological similarity with the original model compound
SAR versus QSAR, History and development of QSAR, Types of physicochemical
parameters, experimental and theoretical approaches for the determination of
physicochemical parameters such as Partition coefficient, Hammet’s substituent
constant and Taft’s steric constant. Hansch analysis, Free Wilson analysis, 3D-QSAR
approaches like COMFA and COMSIA.
THE PRODRUG DESIGNING FOR NEW SELECTION AND FORMULATION OF DRUG COMPATIBLE WITH API I.E. ACTIVE PHARMACUTICAL INGREDIENT, AND ITS EFFECT WHICH SHOULD BE 0. THE DRUG COMBINED WITH API AND AVILABLE IN MARKET AND DRUGS NEED TO BE COMBINE ARE ALSO DISCUSSED WITH ITS STRUCTURE AND SAR, AND COVERED AS PER THE SYLLABUS OF PCI.
Analog design is usually defined as the modification of a drug molecule or of any bioactive compound in order to prepare a new molecule showing chemical and biological similarity with the original model compound
SAR versus QSAR, History and development of QSAR, Types of physicochemical
parameters, experimental and theoretical approaches for the determination of
physicochemical parameters such as Partition coefficient, Hammet’s substituent
constant and Taft’s steric constant. Hansch analysis, Free Wilson analysis, 3D-QSAR
approaches like COMFA and COMSIA.
Quantitative structure - activity relationship (QSAR)
Why QSAR?
costs – 800M$ to bring a new drug to market
Patent life time is limited (generic drugs)
Synthesis / Purification of compounds is expensive and time consume-able
It is like find a needle in the haystack
QSAR helps for focusing most promising drug candidates
QSAR is a mathematical relationship between a “biological activity of a molecular system” and its “geometric and chemical characteristics”.
Such relationships holds – Equations can be drawn up- some confidence
to which should be Fit to the target
QSAR what actually do?
IDENTIFY AND QUANTIFY the Physico-chemical properties effect on Drug’s Biological activity
Aims
To relate the biological activity of a series of compounds to their physicochemical parameters in a quantitative fashion using a mathematical formula
Requirements
Quantitative measurements for biological and physicochemical properties
Physicochemical Properties
Hydrophobicity of the molecule
Hydrophobicity of substituents
Electronic properties of substituents
Steric properties of substituents
QSAR equations are only applicable to compounds in the same structural class (e.g. ethers)
However, log Po is similar for anaesthetics of different structural classes (ca. 2.3)
Structures with log P ca. 2.3 enter the CNS easily
(e.g. potent barbiturates have a log P of approximately 2.0)
Can alter log P value of drugs away from 2.0 to avoid CNS side effects
Physical properties are measured for the molecule as a whole
Properties are calculated using computer software
No experimental constants or measurements are involved
Properties are known as ‘Fields’
Steric field - defines the size and shape of the molecule
Electrostatic field - defines electron rich/poor regions of molecule
Hydrophobic properties are relatively unimportant
No reliance on experimental values
Can be applied to molecules with unusual substituents
Not restricted to molecules of the same structural class
Predictive capability
Comparative molecular field analysis (CoMFA) - Tripos
Build each molecule using modelling software
Identify the active conformation for each molecule
Identify the pharmacophore
THANKING YOU
Richard's entangled aventures in wonderlandRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Richard's aventures in two entangled wonderlandsRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Multi-source connectivity as the driver of solar wind variability in the heli...Sérgio Sacani
The ambient solar wind that flls the heliosphere originates from multiple
sources in the solar corona and is highly structured. It is often described
as high-speed, relatively homogeneous, plasma streams from coronal
holes and slow-speed, highly variable, streams whose source regions are
under debate. A key goal of ESA/NASA’s Solar Orbiter mission is to identify
solar wind sources and understand what drives the complexity seen in the
heliosphere. By combining magnetic feld modelling and spectroscopic
techniques with high-resolution observations and measurements, we show
that the solar wind variability detected in situ by Solar Orbiter in March
2022 is driven by spatio-temporal changes in the magnetic connectivity to
multiple sources in the solar atmosphere. The magnetic feld footpoints
connected to the spacecraft moved from the boundaries of a coronal hole
to one active region (12961) and then across to another region (12957). This
is refected in the in situ measurements, which show the transition from fast
to highly Alfvénic then to slow solar wind that is disrupted by the arrival of
a coronal mass ejection. Our results describe solar wind variability at 0.5 au
but are applicable to near-Earth observatories.
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.
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.
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...
QSAR applications: Hansch analysis and Free Wilson analysis, CADD
1. C O M P U T E R
A I D E D D R U G
D E S I G N
SEMINAR ON
QUANTITATIVE STRUCTURE
ACTIVITY RELATIONSHIPS:
“APPLICATIONS”
GAGAN S
Govt. College of Pharmacy, Bengaluru
Dept. of Pharmaceutical Chemistry.
2. CONTENTS:
• Definition of Hansch analysis
• Physicochemical parameters
• Hansch analysis
• Free-Wilson analysis
• Relation between Hansch and Free-Wilson analysis
3. What is “HANSCH ANALYSIS” ?
Hansch analysis make attempts to mathematically relate
drug activity to measurable chemical properties.
It is a statistical method used to correlate
physicochemical parameters (also called descriptors)with
biological activity.
5. LIPOPHILICITY FACTORS:
Partition coefficient: (log P)
• Refers to the whole molecules.
• Linear relationship between P and drug activity.
Log 1/C = K1 log P + K2
• Parabolic form over large ranges.
6. • Log P0 represents the optimum partition coefficient for
biological activity.
• Parabolic relationships could be represented by
log (1/C) = -k1(log P)2 + k2logP + k3
• Where K1, K2 and K3 are constants that are normally
determined by regression analysis.
7. Lipophilic substituent constants: ( )
• Lipophilicity of substituent groups not of the whole
molecule.
= log PRH - log PRX
PRH = Partition coefficient of the standard compound.
PRX = Partition coefficient of the monosubstituted
derivative.
• What is its value in case of several substituents?
8. ELECTRONIC EFFECTS:
• The Hammett constant ( ):
• The distribution of electrons within a molecule depends on the
nature of the electron withdrawing and donating groups found in
that structure.
• Hammett used this concept to calculate what are now known
as Hammett constants ( x) for a variety of monosubstituted
benzoic acids.
9. X = log (KBX/KB)
X = log KBX – log KB
Where KB and KBX are the equilibrium constants for benzoic
acid and mono substituted benzoic acids respectively.
What the values of X tell about?
10. STERIC EFFECTS:
The Taft steric parameter (Es):
• Taft (1956) used the relative rate constants of the acid catalysed
hydrolysis of a-substituted methyl ethanoates to define his steric
parameter.
• He used methyl ethanoate as his standard and defined Es as:
Es = log(k(XCH2COOCH3))/(k(CH3COOCH3))
Es= logk(XCH2COOCH3) - logk(CH3COOCH3)
11. Molar refractivity:
The molar refractivity is a measure of both the volume of a
compound and how easily it is polarized.
Where n is the refractive index, M the relative mass and ρ the
density of the compound.
12. HANSCH ANALYSIS
Hansch postulated that the biological activity of a drug
could be related to three parameters by simple
mathematical relationships based on the general format:
Log 1/C = k1 (partition parameter) + k2(electronic
parameter) + K3(steric parameter) + K4
13. • If the range of hydrophobicity values are limited to a small range
then the equation will be linear as follows
Log 1/C = K1 log P + K2 + K3Es + k4
• If the log P values are spread over a large range then the
equation will be parabolic
Log 1/C = - K1 log P2 + K2 log P + K3 + K4Es + k5.
• The constants K1 – K5 are determined by computer software in
order to get the best fitting equation.2
14. • Not all the parameters will necessarily be significant.
• For example, the adrenergic blocking activity of 13-Halo-
arylamines was related to and and did not include a steric
factor.2
• The accuracy of a hansch equation may be assured from the
values of the standard deviations (s) and the regression
constant (r).
• The value of the correlation coefficient (r) is a measure of how
closely the data matches the equation.
15. Examples:
This equation tells us that biological activity increase if the
substituents have a positive value and a negative value. In
other words, the substituents be hydrophobic and electron
donating.
16.
17. • Hansch equations may be used to predict the activity of an as
yet un-synthesized analogue.
• This enables the medicinal chemist to make an informed
choice as to which analogues are worth synthesizing.
Limitations:
• Conformational changes in receptor are ignored.
• Metabolism of drug is not considered.
• The potency – lipophilicity relationship may be parabolic or
linear.
18. Advantages:
• The use of descriptors collected from simple chemical systems
can be utilized for prediction of biological activity in complex
systems.
• The predictions are quantitative with statistical confidence limits.
• The method is easy to use and inexpensive.
19. CRAIG PLOTS:
• Craig plots are two dimensional plots of one parameter against
another.
• The plot is divided into four sections corresponding to the
positive and negative values of the parameters.
• They are used, in conjunction with an already established
Hansch equation to select the aromatic substituents that are
likely to produce highly active analogues.
20.
21. • For example, suppose that a Hansch analysis carried out on a
series of aromatic compounds yields the Hansch equation:
Log 1/C = 2.67 - 2.56 + 3.92
• To obtain a high value for the activity (1/C) it is necessary to
pick substituents with a positive value and a negative value.
22. FREE-WILSON ANALYSIS
It is a true structure activity relationship model in which biological
activity of a compound is the sum of the contribution of all the
substituents and the parent moiety.
23. It is based on the following assumptions:
• The entire drug list should have the same parent structure.
• The substitution pattern in various derivatives has to be same.
• The substitutions have to contribute to the biological activity
additively.
24. Therefore, Free Wilson Analysis (FWA) is additive mathematical
model in which a particular substituent in a specific position is
assumed to make an additive and constant contribution to the
biological activity of a molecule in a series of chemically related
molecules.3
25. Log 1/C = Σ (ai Ii) + µ
I = The substituent
ai = Contribution of the substituent
Ii = Contribution of the parent structure
µ = Average activity
27. Advantages of FWA:
• It is simpler, faster and cheaper method where no substituent
constants , , Es are not required.
• Efficiency of the method is high with greater complexity of the
structure.
• The substituent which can or cannot fulfil the principle of
additively can be recognised.
28. RELATIONSHIP BETWEEN HANSCH AND
FREE WILSON ANALYSIS:
• Hansch analysis uses different physicochemical properties to
correlate structure activity relationships in a quantitative way.
• Free Wilson uses different substituents at different positions and
their individual effect on the biological activity.
• Comparatively, Free Wilson method is simple, fast method as
there is no need to calculate physicochemical parameters.
29. • But, in free Wilson analysis, prediction of activity for other
substituents is not possible. Secondly, the assumed
independence of the influence of the substituens on total activity
is often not seen in practice.
• One can use either Hansch or Free Wilson analysis or both to
predict the activity of new molecules before their synthesis.
