1. Structure-based drug design relies on knowledge of the three-dimensional structure of the biological target obtained through methods such as x-ray crystallography. Candidate drugs that are predicted to bind with high affinity and selectivity to the target can be designed.
2. Structure-based drug design approaches include receptor-based drug design, which involves "building" ligands within the constraints of the binding pocket, and ligand-based drug design.
3. De novo drug design is a receptor-based approach that uses the target's 3D structure to design new molecules without existing leads. It involves building ligands that complement the active site properties through manual or automated methods.
molecular docking its types and de novo drug design and application and softw...GAUTAM KHUNE
This ppt deals with all the aspects related to molecular docking ,its types(rigid ,flexible and manual) and screening based on it and also deals with de novo drug design , various softwares available for docking methodologies and applications for molecular docking in new drug design
molecular docking its types and de novo drug design and application and softw...GAUTAM KHUNE
This ppt deals with all the aspects related to molecular docking ,its types(rigid ,flexible and manual) and screening based on it and also deals with de novo drug design , various softwares available for docking methodologies and applications for molecular docking in new drug design
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
In silico drug designing is the drug design which can be carried out in silicon chip,i.e., within computers. The slides are helpful to know a brief description about in silico drug designing.
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
In silico drug designing is the drug design which can be carried out in silicon chip,i.e., within computers. The slides are helpful to know a brief description about in silico drug designing.
Overview of computer aided drug designing.
Clinical and Pre-clinical trials.
Prediction of properties and Drug-likeness.
Advanced treatments of protein-ligand binding.
Summary
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and offering a wide range of dental certified courses in different formats.
CADD is a mixture of bioinformatics and computer science where the information from bioinformatics is combined into a software which makes it easier to process.
A QSAR is a mathematical relationship between a biological activity of a molecular system and its geometric and chemical characteristics.
QSAR attempts to find consistent relationship between biological activity and molecular properties, so that these “rules” can be used to evaluate the activity of new compounds.
Hey students here i am attaching the powerpoint presenatation on the Receptor/enzyme-interaction and its analysis, Receptor/enzyme cavity size prediction, predicting
the functional components of cavities and the concept regarding the fragment based drug design.
Pharmacy students to you will learn principles of drug discovery molecular docking, systematic and simple approach.
Molecular recognition plays a key role in drug receptor interactions, drug activity depends on the molecular binding of the ligand to the receptor binding site.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
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These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
2. 1- Serendipity
2- From natural sources
3- Screening
4- Chemical modification of known drugs
5- Observation of side effects
6- Rational
2
3. Rational drug design
Drug design, or rational drug design or simply rational design, is
the inventive process of finding new medications based on the
knowledge of a biological target.
Drug design involves the design of small molecules that are
complementary in shape and charge to the bio molecular target
with which they interact and therefore will bind to it.
3
4. Finally, drug design that relies on the knowledge of the three-
dimensional structure of the bio molecular target is known as
structure-based drug design.
4
5. INTRODUCTION TO SBDD
Structure-based drug design (or direct drug design) relies on
knowledge of the three dimensional structure of the biological target
obtained through methods such as x-ray crystallography.
X-ray Crystallography 5
6. Using the structure of the biological target, candidate drugs
that are predicted to bind with high affinity and selectivity
to the target may be designed using interactive graphics and
the intuition of a medicinal chemist.
If an experimental structure of a target is not available, it may
be possible to create a homology model of the target based on
the experimental structure of a related protein.
6
7. structure-based drug design can be divided
roughly into two categories:
1. Ligand based Drug Design
2. Receptor based Drug Design
7
8. RECEPTOR BASED DRUG DESIGN
One of the category of structure-based drug design methods is
about “building” ligands, which is usually referred as receptor-
based drug design.
In this case, ligand molecules are built up within the constraints
of the binding pocket by assembling small pieces in a stepwise
manner.
These pieces can be either individual atoms or molecular
fragments.
The key advantage of such a method is that novel structures,
not contained in any database, can be suggested. 8
9. Different approaches based on structural availibility
Receptor Ligand Approach Comments
known known DOCK receptor
based
Programmes-
AUTO-DOCK
known unknown De novo based GROW, LEGEND
LUDI
unknown known Ligand based QSAR
unknown unknown Combinational
based
9
10. DE NOVO APPROACHES
• De novo design is the approach to build a customized
Ligand for a given receptor.
• This approach involves the ligand optimization.
• Ligand optimization can be done by analyzing protein active
site properties that could be probable area of contact by the
ligand.
• The analyzed active site properties are described to
negative image of protein such as hydrogen bond, hydrogen
bond acceptor and hydrophobic contact region.
10
11. DE NOVO DRUG DESIGN
De novo means start afresh, from the beginning, from
the scratch.
It is a process in which the 3D structure of receptor is used
to design newer molecules.
It involves structural determination of the lead target
complexes and lead modifications using molecular
modeling tools.
Information available about target receptor but no existing
leads that can interact.
11
12. Procedure
• Crystallise target protein with bound ligand
• (e.g. enzyme + inhibitor or ligand)
• Acquire structure by X-ray crystallography
• Identify binding site (region where ligand is bound)
• Remove ligand
• Identify potential binding regions in the binding site
• Design a lead compound to interact with the binding
site
• Synthesise the lead compound and test it for activity
• Crystallise the lead compound with target protein and
identify the actual binding interactions
• Structure based drug design
12
13. Types of De Novo Drug Design
And
Differences
Manual Design Automated Design
slow much faster
A single novel structure large numbers of diverse structures
13
14. Disadvantages
• The position of atoms in the crystal structure is accurate only
to 0.2–0.4 A and allowance should be made for that.
• It is possible that the designed molecule may not bind
to the binding site exactly as predicted.
• It is worth leaving scope for variation and elaboration
of the molecule. This allows fine tuning of the molecule's
binding affinity and pharmacokinetics.
14
15. Impotant Points In De Novo Drug Design
• Flexible molecules are better than rigid molecules.
• It is pointless designing molecules which are difficult
or impossible to synthesize.
• Similarly, it is pointless designing molecules which need
to adopt an unstable conformation in order to bind.
• Consideration of the energy losses involved in water desolvation
should be taken into account.
• There may be subtle differences in structure between receptors and
enzymes from different species. This is significant if the structure
of the binding site used for de novo design is based on a protein that
is not human in origin.
15
16. Problems of Automated De Novo
• automated de novo drug design is prone to generating
structures which are either difficult or impossible to
synthesize.
• automated de novo programs revolves around the
scoring functions used to estimate binding affinities.
16
17. Applications
• Design of HIV 1 protease inhibitors
• Design of bradykinin receptor antagonist
• Catechol ortho methyl transferase inhibitors
• Estrogen receptor antagonist
Structure of enzyme Enzyme with inhibitor
17
18. METHOD PROGRAMS AVAILABLE
Site point connection method LUDI
Fragment connection method SPLICE, NEW LEAD,
PRO-LIGAND
Sequential build up methods LEGEND, GROW, SPORUT
Random connection and
disconnection methods
CONCEPTS, CONCERTS, MCDNLG
18
19. LUDI
Stage 1: identification of interaction sites
Stage 2: fitting molecular fragments
Stage 3: fragment bridging
19
20. Stage 1: Identification of interaction sites
The atoms present in the binding site are analysed to identify those that can
take part in hydrogen bonding interactions, and those that can take part in
van der Waals interactions.
20
21. Examples
Identifi cation of aliphatic interaction sites around a methyl group (LUDI).
• The program would identify the carbon of that group as an aliphatic carbon
capable of taking part in van der Waals interactions.
• This is a non-directional interaction, so a sphere is constructed around the carbon
atom with a radius corresponding to the ideal distance for such an interaction(4 A).
• A number of points are placed over the surface of the sphere to define aliphatic
interaction sites.
• Regions of the sphere which overlap or come too close to atoms making up the
binding site are rejected.
• The remaining points are used as the aliphatic interaction sites.
21
22. Identifying interaction sites for hydrogen bonds is carried out in
a different fashion.
• As hydrogen bonds are directional, it is important to define not only the
distance between the ligand and the binding region, but also the relevant
orientation of the atoms.
• This can be done by defining the hydrogen bond interaction site as a vector
involving two atoms.
• The position of these atoms is determined by the ideal bond lengths and bond
angles for a hydrogen bond.
22
23. Stage 2: fitting molecular fragments
• The LUDI program accesses a library of several hundred molecular fragments.
• The molecules chosen are typically 5–30 atoms in size and are usually rigid in
structure because the fitting procedure assumes rigid fragments.
• Some fragments are included which can adopt different conformations.
23
24. • The methyl carbons of an acetone fragment are defined as aliphatic and can
only be fitted onto aliphatic interaction sites.
• The carbonyl group is defined as a hydrogen bond acceptor and can only be
fitted onto the corresponding interaction site.
24
25. • Th e best fit will be the one that matches up the fragment with the
maximum number of interaction sites.
• The program can ‘try out’ the various fragments in its library and
identify those that can be matched up or fitted to the available
interactionsites in the binding site.
25
26. Stage 3: fragment bridging
• Fragments have been identified and fitted to the binding site, the final stage is
to link them up.
• The program first identifies the molecular fragments that closest to each other
in the binding site, then identifies the closest hydrogen atoms.
• These now define the link sites for the bridge. The program now tries out
various molecular bridges from a stored library to find out which one fits best.
• A suitable bridge has been found, a final molecule is created.
26
27. SPROUT
• Like LUDI , the program fits fragments to interaction sites, but there are
differences in the way that the process is carried out.
• Uses templates to represent molecular fragments.
• Each template is defined by vertices and edges, rather than by atoms and bonds.
• A vertex represents a generalized sp-, sp2, sp3 hybridized atom.
• An edge represents a single, double, or triple bond, depending on the
hybridization of the vertices at either end.
27
28. Stages of the generation of the structures
1- Generate fragment templates that will fit the binding site.
The program selects a fragment template randomly and positions it into the binding
site by placing one of the vertices at the center of a sphere.
Fragment templates are placed at all the spheres and grown towards each other until
they are finally linked.
28
29. 2- Create specific molecules from the molecular templates that have been
produced.
This involves replacing the vertices with suitable atoms to allow favourable hydrogen
bonding and vander waals interactions whith the binding site.
29
30. • It radically cuts down the number of different fragments that have to be stored in
the program, making the search for novel structures more efficient.
• The growth of fragment templates allows a molecular template to be constructed
which bridges interaction sites that are some distance apart.
In the LUDI methode, single fragments are placed at each interaction point and
are then linked. If there is a large seperation between the interaction sites, there
might not be a sufficiently long linker to connect the fragments.
30
31. • Sprout has the capacity to identify certain structural features that might be
unrealistic and then modify them.
For example, an OH might be generated during the second stage in order to
introduce a hydrogen bond donor, but if the OH is linked to a double bond this
results in an enol which would tautomerize to a ketone. The latter would not be
able to act as a hydrogen bond donor. The programme can identify an enol and
modify it to a carboxylic acid which can still act as a hydrogen bond donor.
31
32. • The programe also has the ability to modify structures such that they are more
readily synthesized.
For example, introducing a heteroatom into a two-carbon link between two rings
generates a structure which can be more readily synthesized.
• The strucures that are finally generated by sprout are then evaluated in silico for a
variety of properties, including possible toxicity and pharmacokinetic properties.
32
33. LEGEND
A grid is set up within the binding site to identify steric and electrostatic
interaction energies between each grid point and the binding site.
33
34. • These are tabulated for different types of atom and are used to estimate
vander waals interactions for the growing skeletons that are generated by
the program, as well as for structure optimization of final structures.
• The operator has the choice of starting from a single heteroatom, placed
in such a position that it can form a hydrogen bond with the binding site.
DIFFERENCE
Unlike LUDI and SPROUT, LEGEND does not use
fragments or templates to generate skeletons.
34
35. GROW
It is a program that uses molecular fragments to generate novel ligands for
binding sites. The fragments used represent aminoacides and so the
structures that are generated are limited to peptides.
SYNOPSIS
It is designed to generate synthetically feasible structures. Fragments can
only be linked if there is a known reaction which will allow it.
35
36. Although a relatively new design method, de novo design will play
an ever-increasing role in modern drug design. Though yet not able
to automatically generate viable drugs by itself, it is able to give
rise to novel and often unexpected drugs.
Rather slow and inefficient.
Ignores synthetic feasibility while constructing structures.
Cannot be a sole basis for drug design.
36
37. 37
The number and variety of structures which could be identified are
limitless and so the chances of hitting the ideal structure are poor.
There is far more to drug design than finding structure that binds
strongly to its target.
It does not identify whether the structures identified will have
favourable pharmacokinetic properties or acceptable safety profiles.
It can stimulate new ideas and identify novel lead structures which
could then be optimized through structure-based drug design.