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.
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.
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.
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
THE DRUG DESIGN AND DEVELOPMENT BASED ON DRUG DISCOVERY ,HERE ITS NEED RATIONALE ARE EXPLAINED ALSO QSAR, MOLECULAR DOCKING ITS HISTORY NEED, STRUCTURE BASED DRUG DESIGN IN EASY WAY WE HAVE MENTIONED. THIS WILL MAKE READERS EASY TO COLLECT DATA AT A PLACE ALL OVER THIS IS FOR PHARMA STUDENTS, ACADEMICS, PROFESSIONL AND OST USEFUL FOR RESEARCHERS.
THANK YOU
HOPE YOU WILL LIKE AND SHARE
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.
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
THE DRUG DESIGN AND DEVELOPMENT BASED ON DRUG DISCOVERY ,HERE ITS NEED RATIONALE ARE EXPLAINED ALSO QSAR, MOLECULAR DOCKING ITS HISTORY NEED, STRUCTURE BASED DRUG DESIGN IN EASY WAY WE HAVE MENTIONED. THIS WILL MAKE READERS EASY TO COLLECT DATA AT A PLACE ALL OVER THIS IS FOR PHARMA STUDENTS, ACADEMICS, PROFESSIONL AND OST USEFUL FOR RESEARCHERS.
THANK YOU
HOPE YOU WILL LIKE AND SHARE
Insilico methods for design of novel inhibitors of Human leukocyte elastaseJayashankar Lakshmanan
Oral contributed paper “Insilico methods for design of novel inhibitors of Human leukocyte elastase” in the International conference on Systemics, Cybernetics and Informatics-2006
A substituent effect is the change in a molecule’s reactivity when a substituent on the molecule is changed. In 1935, Louis Hammett designed a scale to measure influence of various substituents (X) at the meta- or para- positions on the acidity of benzoic acid.
Contributed by: Erika Aoyama and Megan Browning, University of Utah, 2016
Introduction of QSAR, Steps involved in QSAR, Hansch Analysis, Free Wilson Analysis, Mixed Approach method, Advantage,Disadvantage and Application of QSAR.
(May 29th, 2024) Advancements in Intravital Microscopy- Insights for Preclini...Scintica Instrumentation
Intravital microscopy (IVM) is a powerful tool utilized to study cellular behavior over time and space in vivo. Much of our understanding of cell biology has been accomplished using various in vitro and ex vivo methods; however, these studies do not necessarily reflect the natural dynamics of biological processes. Unlike traditional cell culture or fixed tissue imaging, IVM allows for the ultra-fast high-resolution imaging of cellular processes over time and space and were studied in its natural environment. Real-time visualization of biological processes in the context of an intact organism helps maintain physiological relevance and provide insights into the progression of disease, response to treatments or developmental processes.
In this webinar we give an overview of advanced applications of the IVM system in preclinical research. IVIM technology is a provider of all-in-one intravital microscopy systems and solutions optimized for in vivo imaging of live animal models at sub-micron resolution. The system’s unique features and user-friendly software enables researchers to probe fast dynamic biological processes such as immune cell tracking, cell-cell interaction as well as vascularization and tumor metastasis with exceptional detail. This webinar will also give an overview of IVM being utilized in drug development, offering a view into the intricate interaction between drugs/nanoparticles and tissues in vivo and allows for the evaluation of therapeutic intervention in a variety of tissues and organs. This interdisciplinary collaboration continues to drive the advancements of novel therapeutic strategies.
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.
Deep Behavioral Phenotyping in Systems Neuroscience for Functional Atlasing a...Ana Luísa Pinho
Functional Magnetic Resonance Imaging (fMRI) provides means to characterize brain activations in response to behavior. However, cognitive neuroscience has been limited to group-level effects referring to the performance of specific tasks. To obtain the functional profile of elementary cognitive mechanisms, the combination of brain responses to many tasks is required. Yet, to date, both structural atlases and parcellation-based activations do not fully account for cognitive function and still present several limitations. Further, they do not adapt overall to individual characteristics. In this talk, I will give an account of deep-behavioral phenotyping strategies, namely data-driven methods in large task-fMRI datasets, to optimize functional brain-data collection and improve inference of effects-of-interest related to mental processes. Key to this approach is the employment of fast multi-functional paradigms rich on features that can be well parametrized and, consequently, facilitate the creation of psycho-physiological constructs to be modelled with imaging data. Particular emphasis will be given to music stimuli when studying high-order cognitive mechanisms, due to their ecological nature and quality to enable complex behavior compounded by discrete entities. I will also discuss how deep-behavioral phenotyping and individualized models applied to neuroimaging data can better account for the subject-specific organization of domain-general cognitive systems in the human brain. Finally, the accumulation of functional brain signatures brings the possibility to clarify relationships among tasks and create a univocal link between brain systems and mental functions through: (1) the development of ontologies proposing an organization of cognitive processes; and (2) brain-network taxonomies describing functional specialization. To this end, tools to improve commensurability in cognitive science are necessary, such as public repositories, ontology-based platforms and automated meta-analysis tools. I will thus discuss some brain-atlasing resources currently under development, and their applicability in cognitive as well as clinical neuroscience.
A brief information about the SCOP protein database used in bioinformatics.
The Structural Classification of Proteins (SCOP) database is a comprehensive and authoritative resource for the structural and evolutionary relationships of proteins. It provides a detailed and curated classification of protein structures, grouping them into families, superfamilies, and folds based on their structural and sequence similarities.
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.
This pdf is about the Schizophrenia.
For more details visit on YouTube; @SELF-EXPLANATORY;
https://www.youtube.com/channel/UCAiarMZDNhe1A3Rnpr_WkzA/videos
Thanks...!
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.
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.
Cancer cell metabolism: special Reference to Lactate PathwayAADYARAJPANDEY1
Normal Cell Metabolism:
Cellular respiration describes the series of steps that cells use to break down sugar and other chemicals to get the energy we need to function.
Energy is stored in the bonds of glucose and when glucose is broken down, much of that energy is released.
Cell utilize energy in the form of ATP.
The first step of respiration is called glycolysis. In a series of steps, glycolysis breaks glucose into two smaller molecules - a chemical called pyruvate. A small amount of ATP is formed during this process.
Most healthy cells continue the breakdown in a second process, called the Kreb's cycle. The Kreb's cycle allows cells to “burn” the pyruvates made in glycolysis to get more ATP.
The last step in the breakdown of glucose is called oxidative phosphorylation (Ox-Phos).
It takes place in specialized cell structures called mitochondria. This process produces a large amount of ATP. Importantly, cells need oxygen to complete oxidative phosphorylation.
If a cell completes only glycolysis, only 2 molecules of ATP are made per glucose. However, if the cell completes the entire respiration process (glycolysis - Kreb's - oxidative phosphorylation), about 36 molecules of ATP are created, giving it much more energy to use.
IN CANCER CELL:
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
introduction to WARBERG PHENOMENA:
WARBURG EFFECT Usually, cancer cells are highly glycolytic (glucose addiction) and take up more glucose than do normal cells from outside.
Otto Heinrich Warburg (; 8 October 1883 – 1 August 1970) In 1931 was awarded the Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme.
WARNBURG EFFECT : cancer cells under aerobic (well-oxygenated) conditions to metabolize glucose to lactate (aerobic glycolysis) is known as the Warburg effect. Warburg made the observation that tumor slices consume glucose and secrete lactate at a higher rate than normal tissues.
1. Presented By:
Akshay Avinash Kank.
( M. Pharm II nd Semester )
Guided By:
Dr. S. R. Butle
(M.Pharm, PhD)
School Of Pharmaceutical
Sciences, SRTMU, Nanded.
QSAR MODELS
3. Hansch Analysis
Extra thermodynamic approach
Hansch analysis correlates biological activity values
with physicochemical properties by linear, linear
multiple, or non-linear regression analysis.
Thus Hansch analysis is indeed a property-property
relationship model.
Early attempts to correlate biological activity values
with lipophilicity expressed e.g. by solubility or
partition coefficients only explained nonspecific
structure activity relationships, the application of the
concept of a general biological hammett equation
failed.
The methodological breakthrough came from a
suggestion by Fujita, of that time working in hansch’s
group.
4. Hansch Analysis
Hansch and Fujita combined different physico-
chemical parameters in one equation.
Where, C – Molar concentration
k1, k2, k3, – Coefficients determined by least squares
procedure
For in vivo parabolic lipophilicity values in included in
above equation, hence it becomes
5. Hansch Analysis
Later to this, steric parameters were added to this
general model and even latter molar refractivity
values.
With such multiparameter equation it was
possible to describe much more complex
dependence of biological activities on physico-
chemical properties.
In the last three decades nearly all conceivable
combinations of lipophilic, polarizability, electronic
and steric parameters with or without additional
indicator variables have been used and
correlated with biological activity values in linear,
parabolic and bilinear equation.
6. Application
Hansch analysis can be used to describe
complex biological data, where several different
transport processes and equilibria contribute to
the overall structural activity relationship.
However, in industrial practice such relationships
and their quantitative description are of almost
importance.
Instead of wasting thousands of animals
nowadays enzyme inhibition, receptor binding
and cell culture data are used to derive the
activity profiles of large classes of compounds
and to predict the pharmacodynamic effects of
new drugs from simple and efficient in-vitro test
7. Application- Enzyme inhibition
Significant progress in QSAR resulted from
Hansch analyses of enzyme inhibitors, especially
from the systematic work of Hansch and his
group on dihydrofolate reductase and on cysteine
and serine protease.
Most of our current knowledge of the quantitative
aspects of ligand-protein interactions has been
derived from QSAR equations, aided by the
interpretation of the 3D structures of enzymes
and their inhibitor complexes with molecular
graphics.
8. Application- Enzyme inhibition
3D structures of binary and tertiary DHFR
complexes from different bact. and vertibrates
have been published and an extremely large
number of QSAR equations have been derived
both for the isolated enzyme and for growth
inhibition of whole cells.
Due to the central role of DHFR in purine
biosynthesis, DHFR inhibitors are therapeutically
important as highly selective antibacterial
(trimethoprim) and antitumor agents
(methotrexate).
9. Application- Other in-vitro data
Hansch analysis provides the data for binding
affinities to the –
Beta-adrenergic receptor
Benzodiazepine receptor
Tetrachlorodibenzoodioxin receptor
Dopamine receptor
Hansch concluded that a change in the
membrane properties should be responsible for
the drug resistance.
So the multidrug resistance can be overcome by
Hansch quantitative models.
10. Application- Pharmacokinetic
data
Pharmacokinetics describes the time dependence of
transport and distribution of a drug in the different
compartments of biological system.
Model simulations substantiate that the lipophilicity
dependence of the rate constants of drug transport
should follows bi-linear relationships.
Indeed, bi-linear equations have been derived for the
rate constant of drug transport in n-octanol/water
and for the rate constants of the transfer of various
barbiturates in a Sartorius absorption simulator from
an aqueous phase(pH-3) through an organic
membrane to another aqueous phase(pH-7.5)
modeling the gastric absorption of these compounds.
11. Free-Wilson analysis
The additivity model
The version described by Fujita and Ban is a
straightforward application of the additivity concept of
group contributions to biological activity values.
logBA = contribution of unsubstituted parent
compound +
contribution of corresponding substituent
= µ + ∑aij
Where,
i-number of position at which substitution occurs
j-number of substituent at that position
µ-overall average
BA = f(R) +f(R1) +f(R2) +f(R3) +µ
Where,
µ = biological activity of unsubstituted acetylenic
carbamates.
12. Free-Wilson analysis
In comparison with classical version of the free-
Wilson analysis, the Fujita and Ban variant offers
a number of important advantages –
The table for regression analysis can easily be
generated.
The addition and elimination of compounds is
simple and does not change the values of the other
regression coefficients significantly.
Any compound may be chosen as the reference
compound.
Substituents which always occur together in two
different positions of the molecule can be combined
to a pseudo substituent.
13. Free-Wilson analysis
The free-Wilson model is easy to apply.
Especially in the early phase of structure activity
analyses it is simple method to derive substituent
contributions and to have a first look on their
possible dependence on different physico-
chemical properties.
It has some limitations-
Every substituent which only once occurs in the
data set, leads to a single point determination; the
corresponding group contribution contains the
whole experimental error of this one biological
activity value.
14. Free-Wilson analysis
Limitations:
Only a common activity contribution can be
derived for substituents which always occurs
together in two different positions of the
molecules.
In most cases a large number of parameters is
needed to describe relatively few compounds,
sometimes leading to equations which are
statistically not significant.
Only a small number of new analogs can be
predicted from a Free-Wilson analysis .
Prediction for substituents which are not
included in the analysis are generally impossible.
It is limited to linear additive structure activity
relationships.
15. Applications
Different sets of compounds were used in a Free Wilson
analysis of analgesic benzomorphans the first one
included all compounds (38 variables; n = 99; r = 0.893; s
= 0.466), a second one only contained racemic
compounds (36 variables; n = 86; r = 0.909; s = 0.457) and
a last one excluded all single point determinations (20
variables, n = 70; r = 0.879; s = 0.457).
The group contributions of the benzomorphans could be
used to predict the biological activity values of structurally
related morphinans, which are more active than the
benzomorphans by some orders of magnitude.
16. Applications
The simplest form of a Free Wilson analysis is presented
by describing the antibacterial activities of phenol and
isomeric chlorophenols (R = H, C1; one to five chlorine
atoms) us. Staphylococcus aureus; at least the linearity of
the structure-activity relationship can be derived from
below equation. On the other hand, although most
probably lipophilicity is responsible for the variance in the
biological activities, no Hansch equation can be derived,
because each other physicochemical property of the
chlorine atom will give identical results.
17. Applications
Free Wilson analyses may include far fewer variables than
substituents, if group contributions being not significant are
eliminated. Indicator variables for 28 different structural
features and different test models and 15 interaction terms
were investigated to describe the inhibition of dihydrofolate
reductase by 2,4-diaminopyrimidines; 9 indicator variables
and 2 interaction terms were selected and below equation
was derived out of the 2047 theoretically possible linear
combinations of any numbers of these variables.
18. Mixed Approach
This theoretical relationship between Hansch analysis and
the Free Wilson model was first recognized by Singer and
Purcell.
Free Wilson group contributions contain all possible
physicochemical contributions of a substituent;
correspondingly, a Free Wilson analysis always gives the
upper limit of correlation which can be achieved by a linear
Hansch analysis.
A comparison of the results from Hansch and Free Wilson
analyses offers some information, whether a certain Hansch
model can be considered to be acceptable or not. In most
cases the Free Wilson analysis of a data set shows whether
a linear additive model is suited for the analysis; only in
certain cases is a good fit obtained for nonlinear
relationships, especially if there are only few degrees of
19. Mixed Approach
An example, how a Hansch equation can be
improved by comparing the group contributions
with those obtained from Free Wilson analysis, is
given below in equation was derived for the
antifungal activities of phenyl ethers (13, X, Y =
H, OH).
20. Cont’d…
The Free Wilson analysis of the same data set indicates
that the smaller group contributions of the ortho-
substituents might be explained by a steric effect.
Due to the relationships between Hansch analysis and
the Free Wilson model, indicator variables have
relatively early been included in Hansch analyses. Both
models can be combined to a mixed approach, in a
linear and a nonlinear form, which offers the advantages
of both, Hansch analysis and Free Wilson analysis, and
widens their applicability in quantitative structure-activity
relationships.
21. Cont’d…
Kubinyi has presented the combination of Hansch
and Free –Wilson model as “Mixed approach”.
log 1c =K1 л+K2 б+K3Es +K………Hansch
model
log 1c=µ +∑aij………….Free-Wilson approach
log1c=∑aij+∑kj+K……..Mixed approach
Kj represent the coefficient of different physico-
chemical parameters.
Mixed approach was developed to find possible
interaction between Free-Wilson parameters and
physicochemical properties of substituents used.