This document discusses pharmacophore approach in rational drug design. It begins by defining a pharmacophore as an abstract description of molecular features necessary for molecular recognition by a biological macromolecule. It then discusses pharmacophore mapping, methods of pharmacophore screening, and applications. Key steps in developing a pharmacophore model include selecting a training set of ligands, conformational analysis, molecular superposition, abstraction, and validation. Pharmacophore models can be used to retrieve potential drug leads from databases and design new molecules.
Introduction to Genetic Variation in GPCR
G-Protein couple Receptor
Genetic variation in GPCRs
V2 Vasopressin Receptor, Thrombroxane Receptor, P2Y 12ADP Receptor, Chemokine Receptor, Biogenic amine receptors
Presented by
R. REKHA
Department of Pharmacology
The basic aspects of drug discovery starts from target discovery and validation further going to lead identification and optimization. In this particular slide discussion is regarding the target discovery and the tools that have been utilized in this process.
Introduction to Genetic Variation in GPCR
G-Protein couple Receptor
Genetic variation in GPCRs
V2 Vasopressin Receptor, Thrombroxane Receptor, P2Y 12ADP Receptor, Chemokine Receptor, Biogenic amine receptors
Presented by
R. REKHA
Department of Pharmacology
The basic aspects of drug discovery starts from target discovery and validation further going to lead identification and optimization. In this particular slide discussion is regarding the target discovery and the tools that have been utilized in this process.
Extrapolation of in vitro data to preclinical and.pptxARSHIKHANAM4
Extrapolation of in vitro data to preclinical.
the topic is included in m.pharmacy 1st sem syllabus. which is essential for the study and that include the details about how you deal with the preclinical data that will help to decide the NOEAL and LOEAL, the humane dose of the drug can be calculated and further formation is also done.
OECD principles of Good laboratory practice. this ppt include the basic and necessary information required for OECD GLP guideline . Content is taken from official site
Dermal Irritation and Dermal Toxicity Studies Dinesh Gangoda
Dermal irritation and Corrosion test guidelines 204.
Dermal irritation is the production of reversible damage of the skin following the application of a test chemical for up to 4 hours.
Corrosive reactions are typified by ulcers, bleeding, bloody scabs, and, by the end of observation at 14 days, by discolouration due to blanching of the skin, complete areas of alopecia, and scars. Histopathology should be considered to evaluate questionable lesions. [1]
Dermal corrosion is the production of irreversible damage of the skin; namely, visible necrosis through the epidermis and into the dermis, following the application of a test chemical for up to four hours.[2]
REFERENCES
OECD/OCDE, Test No. 404: ‘‘Acute Dermal Irritation/Corrosion’’, 28 July 2015 OECD Publishing, peris, Page no, 1- 8.
Robert A., Turner., Screening Methods in Pharmacology; 1st edition; Academic press an imprint of Elsevier, pp, 279- 281.
OECD Guideline for testing of chemicals (1981). ‘‘Repeated Dose Dermal Toxicity’’, 21/28- day Study.
This guideline was developed to help protect clinical trial participants and patients receiving marketed products from potential adverse effects of pharmaceuticals, while avoiding unnecessary use of animals and other resources. This guideline provides a definition, general principles and recommendations for safety pharmacology studies
ChronoPharmacology in Body Functioning and in Cardiovascular Diseases.pptPayaamvohra1
This ppt gives one an idea about the chronopharmacology and its role i Pharmaceutics as well as Pharmacology.It describes the time dependent cellular processes of body for homeostasis
Regulatory guidelines for conducting toxicity studies by ichAnimatedWorld
ICH is the “International Conference on Harmonization of
Technical Requirements for Registration of Pharmaceuticals for
Human Use”
ICH is a joint initiative involving both regulators and research based industry representatives of the EU, Japan and the US in
scientific and technical discussions of the testing procedures required
to assess and ensure the safety, quality and efficacy of medicines
Extrapolation of in vitro data to preclinical and.pptxARSHIKHANAM4
Extrapolation of in vitro data to preclinical.
the topic is included in m.pharmacy 1st sem syllabus. which is essential for the study and that include the details about how you deal with the preclinical data that will help to decide the NOEAL and LOEAL, the humane dose of the drug can be calculated and further formation is also done.
OECD principles of Good laboratory practice. this ppt include the basic and necessary information required for OECD GLP guideline . Content is taken from official site
Dermal Irritation and Dermal Toxicity Studies Dinesh Gangoda
Dermal irritation and Corrosion test guidelines 204.
Dermal irritation is the production of reversible damage of the skin following the application of a test chemical for up to 4 hours.
Corrosive reactions are typified by ulcers, bleeding, bloody scabs, and, by the end of observation at 14 days, by discolouration due to blanching of the skin, complete areas of alopecia, and scars. Histopathology should be considered to evaluate questionable lesions. [1]
Dermal corrosion is the production of irreversible damage of the skin; namely, visible necrosis through the epidermis and into the dermis, following the application of a test chemical for up to four hours.[2]
REFERENCES
OECD/OCDE, Test No. 404: ‘‘Acute Dermal Irritation/Corrosion’’, 28 July 2015 OECD Publishing, peris, Page no, 1- 8.
Robert A., Turner., Screening Methods in Pharmacology; 1st edition; Academic press an imprint of Elsevier, pp, 279- 281.
OECD Guideline for testing of chemicals (1981). ‘‘Repeated Dose Dermal Toxicity’’, 21/28- day Study.
This guideline was developed to help protect clinical trial participants and patients receiving marketed products from potential adverse effects of pharmaceuticals, while avoiding unnecessary use of animals and other resources. This guideline provides a definition, general principles and recommendations for safety pharmacology studies
ChronoPharmacology in Body Functioning and in Cardiovascular Diseases.pptPayaamvohra1
This ppt gives one an idea about the chronopharmacology and its role i Pharmaceutics as well as Pharmacology.It describes the time dependent cellular processes of body for homeostasis
Regulatory guidelines for conducting toxicity studies by ichAnimatedWorld
ICH is the “International Conference on Harmonization of
Technical Requirements for Registration of Pharmaceuticals for
Human Use”
ICH is a joint initiative involving both regulators and research based industry representatives of the EU, Japan and the US in
scientific and technical discussions of the testing procedures required
to assess and ensure the safety, quality and efficacy of medicines
Pharmacophore models are typically used when some active compounds have been identified, but the 3D structure of the target protein or receptor is unknown.
Several programs have been developed for the automatic identification of pharmacophore models.
The main differences between the programs lie in the algorithms used for the alignment and how conformational flexibility is handled.
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
Pharmacophore Mapping and Virtual Screening (Computer aided Drug design)AkshayYadav176
Pharmacophore Mapping and Virtual Screening (Computer aided Drug design)
Concept of pharmacophore, Pharmacophore mapping, Identification of pharmacophore features and pharmacophore modeling, Conformation search used in pharmacophore mapping, Virtual screening.
CONCEPT OF PHARMACOPHORE
PHARMACOPHORE MAPPING
IDENTIFICATION OF PHARMACOPHORE FEATURE
CONFORMATIONAL SEARCH
INSILICO DRUG DESIGN
VIRTUAL SCREENING
PHARMACOPHORE BASED SCREENING
First introduced by Paul Heritich in 1990
A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule.
It is the key features responsible for an activity (eg. Substrates, inhibitors)
A pharmacophore is a representation of generalized molecular features including;
3D (hydrophobic group, chaeged /ionisable group, hydrogen bond donar/ acceptor)
2D (substructure)
1D (physical & biological)
Pharmacophore Mapping is the definition and placement of pharmacophoric features and the alignment techniques used to overlay 3D.
Two somewhat distinct usages:
That substructure of a molecule that is responsible for its pharmacological activity (c.f. chromophore)
A set of geometrical constraints between specific functional groups that enable the molecule to have biological activity
The process of deriving pharmacophore is known as pharmacophore mapping.
Pharmacophore identification and novel drug designBenittabenny
pharmacophore is a part of a molecular structure that is responsible for a particular biological or pharmacological interaction that it undergoes. This identification leads to the development of designing a new drug.
Synthetic Fiber Construction in lab .pptxPavel ( NSTU)
Synthetic fiber production is a fascinating and complex field that blends chemistry, engineering, and environmental science. By understanding these aspects, students can gain a comprehensive view of synthetic fiber production, its impact on society and the environment, and the potential for future innovations. Synthetic fibers play a crucial role in modern society, impacting various aspects of daily life, industry, and the environment. ynthetic fibers are integral to modern life, offering a range of benefits from cost-effectiveness and versatility to innovative applications and performance characteristics. While they pose environmental challenges, ongoing research and development aim to create more sustainable and eco-friendly alternatives. Understanding the importance of synthetic fibers helps in appreciating their role in the economy, industry, and daily life, while also emphasizing the need for sustainable practices and innovation.
Operation “Blue Star” is the only event in the history of Independent India where the state went into war with its own people. Even after about 40 years it is not clear if it was culmination of states anger over people of the region, a political game of power or start of dictatorial chapter in the democratic setup.
The people of Punjab felt alienated from main stream due to denial of their just demands during a long democratic struggle since independence. As it happen all over the word, it led to militant struggle with great loss of lives of military, police and civilian personnel. Killing of Indira Gandhi and massacre of innocent Sikhs in Delhi and other India cities was also associated with this movement.
A Strategic Approach: GenAI in EducationPeter Windle
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
Acetabularia Information For Class 9 .docxvaibhavrinwa19
Acetabularia acetabulum is a single-celled green alga that in its vegetative state is morphologically differentiated into a basal rhizoid and an axially elongated stalk, which bears whorls of branching hairs. The single diploid nucleus resides in the rhizoid.
The French Revolution, which began in 1789, was a period of radical social and political upheaval in France. It marked the decline of absolute monarchies, the rise of secular and democratic republics, and the eventual rise of Napoleon Bonaparte. This revolutionary period is crucial in understanding the transition from feudalism to modernity in Europe.
For more information, visit-www.vavaclasses.com
Biological screening of herbal drugs: Introduction and Need for
Phyto-Pharmacological Screening, New Strategies for evaluating
Natural Products, In vitro evaluation techniques for Antioxidants, Antimicrobial and Anticancer drugs. In vivo evaluation techniques
for Anti-inflammatory, Antiulcer, Anticancer, Wound healing, Antidiabetic, Hepatoprotective, Cardio protective, Diuretics and
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2024.06.01 Introducing a competency framework for languag learning materials ...Sandy Millin
http://sandymillin.wordpress.com/iateflwebinar2024
Published classroom materials form the basis of syllabuses, drive teacher professional development, and have a potentially huge influence on learners, teachers and education systems. All teachers also create their own materials, whether a few sentences on a blackboard, a highly-structured fully-realised online course, or anything in between. Despite this, the knowledge and skills needed to create effective language learning materials are rarely part of teacher training, and are mostly learnt by trial and error.
Knowledge and skills frameworks, generally called competency frameworks, for ELT teachers, trainers and managers have existed for a few years now. However, until I created one for my MA dissertation, there wasn’t one drawing together what we need to know and do to be able to effectively produce language learning materials.
This webinar will introduce you to my framework, highlighting the key competencies I identified from my research. It will also show how anybody involved in language teaching (any language, not just English!), teacher training, managing schools or developing language learning materials can benefit from using the framework.
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This slides describes the basic concepts of ICT, basics of Email, Emerging Technology and Digital Initiatives in Education. This presentations aligns with the UGC Paper I syllabus.
June 3, 2024 Anti-Semitism Letter Sent to MIT President Kornbluth and MIT Cor...Levi Shapiro
Letter from the Congress of the United States regarding Anti-Semitism sent June 3rd to MIT President Sally Kornbluth, MIT Corp Chair, Mark Gorenberg
Dear Dr. Kornbluth and Mr. Gorenberg,
The US House of Representatives is deeply concerned by ongoing and pervasive acts of antisemitic
harassment and intimidation at the Massachusetts Institute of Technology (MIT). Failing to act decisively to ensure a safe learning environment for all students would be a grave dereliction of your responsibilities as President of MIT and Chair of the MIT Corporation.
This Congress will not stand idly by and allow an environment hostile to Jewish students to persist. The House believes that your institution is in violation of Title VI of the Civil Rights Act, and the inability or
unwillingness to rectify this violation through action requires accountability.
Postsecondary education is a unique opportunity for students to learn and have their ideas and beliefs challenged. However, universities receiving hundreds of millions of federal funds annually have denied
students that opportunity and have been hijacked to become venues for the promotion of terrorism, antisemitic harassment and intimidation, unlawful encampments, and in some cases, assaults and riots.
The House of Representatives will not countenance the use of federal funds to indoctrinate students into hateful, antisemitic, anti-American supporters of terrorism. Investigations into campus antisemitism by the Committee on Education and the Workforce and the Committee on Ways and Means have been expanded into a Congress-wide probe across all relevant jurisdictions to address this national crisis. The undersigned Committees will conduct oversight into the use of federal funds at MIT and its learning environment under authorities granted to each Committee.
• The Committee on Education and the Workforce has been investigating your institution since December 7, 2023. The Committee has broad jurisdiction over postsecondary education, including its compliance with Title VI of the Civil Rights Act, campus safety concerns over disruptions to the learning environment, and the awarding of federal student aid under the Higher Education Act.
• The Committee on Oversight and Accountability is investigating the sources of funding and other support flowing to groups espousing pro-Hamas propaganda and engaged in antisemitic harassment and intimidation of students. The Committee on Oversight and Accountability is the principal oversight committee of the US House of Representatives and has broad authority to investigate “any matter” at “any time” under House Rule X.
• The Committee on Ways and Means has been investigating several universities since November 15, 2023, when the Committee held a hearing entitled From Ivory Towers to Dark Corners: Investigating the Nexus Between Antisemitism, Tax-Exempt Universities, and Terror Financing. The Committee followed the hearing with letters to those institutions on January 10, 202
3. First introduced in 1990 by “Paul Herilich”.
A pharmacophore is an abstract description of
molecular features which are necessary for molecular
recognition of a ligand by a biological
macromolecule.
A pharmacophore is a representation of
generalized molecular features including;
3D (hydrophobic groups, charged/ionizable groups,
hydrogen bond
donors/acceptors)
2D (substructures)
1D (physical or biological)
properties that are considered to be responsible
for a desired biological activity.
3
4. PHARMACOPHOREINDRUGDESIGNAND
DISCOVERY
A pharmacophore model is a geometrical description of the
chemical functionalities required of a ligand to interact with
receptor. Modern medicinal chemistry is to reduce the
overall cost in drug discovery, by identifying the most
promising candidates to focus on the experimental efforts.
Experimental screening for lead structure determination
suffers from limitation with respect to the possible number of
compounds that can be submitted to a high throughput
bioassay and with low number of hits obtained that is in the
range of 0.1%.
The pharmacophore approach has proven to be successful,
Allowing(i) the perception and understanding of key
interaction between a target and a ligand and (ii) the
enrichment of hit rates obtained in experimental screening of
sub sets that have been obtained from in silico screening
experiments. 4
5. Pharmacophore mapping is one of the major
elements of drug design in the absence of
structural data of the target receptor. It can be
used as queries for retrieving potential leads
from the structural databases, for designing
molecules with specific desired attributes and
for assessing similarity and diversity of
molecules using pharmacophore fingerprints.
It can also be used to align molecules based on
the 3D arrangement of chemical features or to
develop predictive 3D QSAR models.
5
6. PROCESSFORDEVELOPINGA
PHARMACOPHOREMODEL
They generally involves the following steps:
Select a training set of ligands – Choose a
structurally diverse set of molecules that will be
used for developing the pharmacophore model. As a
pharmacophore model should be able discriminate
between molecules with and without bioactivity, the
set of molecules should include both active and
inactive compounds.
Conformational analysis- Generate a set of low
energy conformations that is likely to contain
bioactive conformation for each of the selected
molecules.
6
7. Molecular superposition- Superimpose(“fit”) all combination
of the low energy conformation of the molecules. Similar
(bioisosteric) functional groups common to all molecules in
the set might be fitted (e.g. Phenyl rings or carboxylic acid
groups). The set of conformations (one conformations from
each active molecule) that results in the best fit is presumed
to be the active conformation.
Abstraction- Transform the superimposed molecules into an
abstract representation. For example, superimposed phenyl
rings might be referred to more conceptually as an ‘aromatic
ring’ pharmacophore element. Likewise, hydroxy groups
could be designated as a ‘hydrogen –bond donor/acceptor’
pharmavophoreelement.
7
8. Validation- A pharmacophore model is a
hypothesis accounting for the observed
biological activities of a setoff molecules
that bind to a common biological target.
The model is only valid so far as it is able
to account for differences in biological
activity of a range of molecules.
8
9. Pharmacophore Mapping is the definition and
placement of pharmacophoric features and the
alignment techniques used to overlay 3D.
Two somewhat distinct usages:
That substructure of a molecule that is
responsible for its pharmacological activity
(c.f. chromophore)
A set of geometrical constraints between specific
functional groups
that enable the molecule to have biological activity
The process of deriving pharmacophore
is known as pharmacophore mapping.
9
10. It consist of three steps:
(1) identifying common binding element that are
responsible for the biological activity;
(2) generating potential conformations that active
compound may adopt; and
(3) determining the 3D relationship between
pharmacophore element in each conformation
generated.
10
12. The process of finding drug by design.
Based on what the drug targeting?
Metabolic or Signaling pathway
Specific for disease or pathology.
Drugs
Bind to active site & Work.
12
13. Usually pharmacophore based search are done in two
steps.
First the software checks whether the compound has
the atom types or functional groups required by the
pharmacophore,
than its checks whether the spatial arrangement of this
element matches the query.
Flexible 3D searches identified a higher number of hits
than rigid searches do.
However flexible searches are more time consuming than
rigid
ones.
There are two main approaches for including
conformational flexibility in to the search
one is top generate a user defined number of representative
conformation for each molecules when the database is to
created,
the other is to generate conformation during the search.
13
14. Pharmacophore model provide powerful filter tools for
virtual screening even in case where the protein
structure is not available, pharmacophore filter are
much faster than docking approaches, and there for
greatly reduce the number of compound subjected to
the more expensive docking application.
Another interesting aspect of pharmacophore in
virtual screening is 3D- pharmacophore diversity.
14
16. 2-D PHARMACOPHORE
SEARCHING
16
Searching of 2D database is of great importance for
accelerating the drug discovery different strategies are
pursued to search a2D database to identified the
compound of the interest Substructure search
identified larger molecules that contain user define
query irrespective of the environment in which the
query substructure occur.
Biochemical data obtainable from these compounds
can be used for generating structure-activity-
relationship (SAR) even before synthetic plans are
made for leadoptimization.
In contrast, superstructure search are used to
find smaller molecules that are embedded in the
query.
17. Beyond structure similarity, activity similarity
has also been subject of several studies.
Similarity search can be combined with substructure
for limiting
the number of compound selected.
Flexible searches are used to identify the
compound that differs from the query structure in
user-specified ways.
3-D Pharmacophore searching
1.Ligand based pharmacophore generation
Ligand based pharmacophores are generally used
when crystallographic;solution structure or molded
structure of protein cannot be obtained.
When a set of active compound is known and it is
hypothesized that all the compounds bind in the
similar way to the protein, then common group should
interact with the same protein residue.
17
18. Thus, a pharmacophore capturing this compound
feature should be able to identified from a database
novel compounds that binds to the same site of the
protein as the known compounds do.
2. Manual pharmacophore generation
Manual pharmacophore generation is used when there
is an easy way to identify the common feature in a
set of active compounds and/or there is experimental
evidence that same functional groups should be
present in the ligand for good activity.
An example is the development of a
pharmacophore model for dopamine-transporter
(DAT) inhibitor.
Pharmacophores should also have some flexibility
built in, thus
justifying the use of distance ranges.
18
19. 3. Automatic pharmacophore generation
Pharmacophore generation through conformational
analysis and manual alignment is a very time
consuming task, especially when the list of the
active ligands is large and the elements of the
pharmacophore model are not obvious.
There are several programs Hip Hop, Hypogen,
Disco, Gaps, flo, APEX, and ROCS, that can
automatically generate potential pharmacophore
from a list of known inhibitors.
The performance of these programs in automated
pharmacophore generation varies depending on the
training set.
These all program use algorithms that identified the
common pharmacophore features in the training set
molecules; they scoring function to rank the
identified pharmacophores.
19
20. 4. Receptor based pharmacophore generation
If the 3D structure of receptor is known, a
pharmacophore model can be derived based on the
receptor active site.
Biochemical data used to identify the key residue that
is important for substrate and/or inhibiting binding.
This information can be used for binding
pharmacophores targeting the region defined by key
residue or for choosing among pharmacophore
generated by automated program.
This can greatly improve the chance of finding small
molecules that inhibit the protein because the
search is focused on a region of the binding side
that is crucial for binding substrate and inhibitors.
20
22. Discovery studio :
Window ® and Linux® based protein
modeling software.
Produced by Accelrys software company.
Easy to use interface.
Examples of the programs that perform
pharmacophore based searches are 3D search UNITY,
MACCS-3D and ROCS.
ROCS is using as shape based super position
for identifying compound that have similar
shaped.
22