This lecture outlines the different strategies for finding a fragment hit and the subsequent elaboration strategies used in order to increase potency to develop a lead compound in drug discovery.
THE ENERGY MINIMIZATION, FOR THE STUDENTS OF M.PHARM, B.PHARM AND OTHERS USEFUL FOR ACADEMIC TOO. THE PRESENT DATA IS MOST USEFUL FOR PHARMACY PURPOSE.
This lecture outlines the different strategies for finding a fragment hit and the subsequent elaboration strategies used in order to increase potency to develop a lead compound in drug discovery.
THE ENERGY MINIMIZATION, FOR THE STUDENTS OF M.PHARM, B.PHARM AND OTHERS USEFUL FOR ACADEMIC TOO. THE PRESENT DATA IS MOST USEFUL FOR PHARMACY PURPOSE.
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
Quantum Mechanics in Molecular modelingAkshay Kank
This slides gives you the information related to computer aided drug design and its application in drug discovery. Also you learn the Quantum mechanics related to the molecular mechanics. Theory related to molecular modeling and how the molecular modeling helps in drug discovery.
PREDICTION AND ANALYSIS OF ADMET PROPERTIES OF NEW.pptxMO.SHAHANAWAZ
Detail about PREDICTION AND ANALYSIS OF ADMET PROPERTIES OF NEW MOLECULES AND IT’S IMPORTANCE IN DRUG DISCOVERY, including DESCRIPTORS OF ADMET PREDICTION, DATASETS USED IN ADMET PREDICTION
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.
Process chemistry AS PER PCI SYLLABUS FOR M.PHARMShikha Popali
pharmaceutical process chemistry is process WHERE FROM THE RESEARCH TO FINISH PRODUCT INCLUDING THE PRODUCT DEVELOPMENT AT LABORATORY LEVEL THAN PILOT PLANT WHERE THE PRODUCT IS MANUFACTURED IN 10X THAN FINAL AT 100X THAT IS SCALE UP PLANT.
MOLECULAR DOCKING AND DRUG RECEPTOR INTERACTION AGENT ACTING.pptxMO.SHAHANAWAZ
Point to point M.pharm CADD presentation on MOLECULAR DOCKING AND DRUG RECEPTOR INTERACTION AGENT ACTING, Dihydro Folate reductase Inhibiter (Methotrexate)
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.
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
Quantum Mechanics in Molecular modelingAkshay Kank
This slides gives you the information related to computer aided drug design and its application in drug discovery. Also you learn the Quantum mechanics related to the molecular mechanics. Theory related to molecular modeling and how the molecular modeling helps in drug discovery.
PREDICTION AND ANALYSIS OF ADMET PROPERTIES OF NEW.pptxMO.SHAHANAWAZ
Detail about PREDICTION AND ANALYSIS OF ADMET PROPERTIES OF NEW MOLECULES AND IT’S IMPORTANCE IN DRUG DISCOVERY, including DESCRIPTORS OF ADMET PREDICTION, DATASETS USED IN ADMET PREDICTION
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.
Process chemistry AS PER PCI SYLLABUS FOR M.PHARMShikha Popali
pharmaceutical process chemistry is process WHERE FROM THE RESEARCH TO FINISH PRODUCT INCLUDING THE PRODUCT DEVELOPMENT AT LABORATORY LEVEL THAN PILOT PLANT WHERE THE PRODUCT IS MANUFACTURED IN 10X THAN FINAL AT 100X THAT IS SCALE UP PLANT.
MOLECULAR DOCKING AND DRUG RECEPTOR INTERACTION AGENT ACTING.pptxMO.SHAHANAWAZ
Point to point M.pharm CADD presentation on MOLECULAR DOCKING AND DRUG RECEPTOR INTERACTION AGENT ACTING, Dihydro Folate reductase Inhibiter (Methotrexate)
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.
MALDI...
This Presentation Contain following...
#Introduction
#Matrix and examples
#Considerations of Matrix Material
#MALDI Sample Preparation
#Mechanism of MALDI
#Mass Spectrometer
#Reproducibility and Performance
#Uses of MALDI
#Conclusion
#References
Thanks For Help and Guidance of Mr. D.V. Mahuli Sir and Mr. V.T. Pawar Sir
TRAGEDY OF COMMON IN THAT THE PEOPLE ARE HOW USE NATURAL RESOURCES HOW CARELESS ABOUT THAT AND HOW ITS EFFECT ON FUTURE, ENVIRONMENT NATURE , HUMAN AND LIVING SYSTEM
The presentation content Introduction
Objective, Factors affecting layout, Scope of facility of layout, Type of facility of layout and Process designing
Prerequisites for Developing a Facility Layout
Level of plants, Technique for designing a facility layout, Case study with example
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
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.
Follow us on: Pinterest
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
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
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
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
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.
3. INTRODUCTION
Historical development-
• Abbott laboratories pioneered in the introduction of SAR-FBDD by using
NMR, in 1990.
• Followed by HTS crystallography in 2000.
• So, it examine 23 protein by SAR-NMR method with 0-0.9% hit rate for
various sampling.
• They were identify potent <300 µM inhibitor.
• The late 1990s the method was developed as HTL (hit- to- lead).
• ADVANTAGES OF FBBD-
Smaller screning libraries
Higher hit rates
Improve physicochemical properties
Opportunities for chemical novelty
4. Concept and overview-
What is FBBD
• “The construction of smaller , low MW, less complex molecular structure that
presnt only limited no. of pharmacophores and degrees of conformational
freedom” also known as scaffold or templet.
• FBDD based on
FBDD based on
Lipinskis rule-5
not > 5H bond donar, not >
10 H bond accepter, Clog P<
5, MW < 500.
Rule of -3
molecular weight < 300 Da
cLogP < 3,No.of H bond
donors /accepter < 3
Fig : FBDD workflow
6. METHOD FOR FRAGMENT SCREENING
A) IDENTIFICATION OF FRAGMENT HIT-
B) FRAGMENT OPTIMIZATION-
1. NMR- it provide detailed information about the
structure, dynamics, reaction state, and chemical
environment of molecules.
NMR
PROTEIN
DETECTED
NMR
MODERATE
AFFINITY BINDER
Kd- 100µM
HIGH AFFINITY
BINDER Kd -19µM
LIGAND
DETECTED
NMR
SATURATION
TRANSFER
DIFFERENCE-
NMR (STD-NMR)
WATER LIGAND
OPTIMIZED
GRADIENT NMR
(LOGSY)
FLUORINE
CHEMICAL SHIFT
ANISOTROPHY
AND EXCHANGE
FOR SCREENING
(FAXS)
TARGET
IMMOBILISED
NMR( TINS)
7. 2. X- ray crystallography-
Detection of hit fragment by Cocktail
method-
Astex Therapeutics identifie fragments for
the cyclin dependent kinase (CDK) 2
AT7519 and AT9283 Akinase inhibitor for
cancer therapy.
3.Surface Plasmon Resonance-
SPR to identify potent fragment hits against
BACE-1, Pim-1, HIV-1 reverse
transcriptase, HIV-1 protease, carbonic
anhydrase II, human serum albumin,
thrombin, chymase .
8. 4. Biolayer interferometry-
BLI it measures changes in the interference
pattern of light between the sensor and the
solution.
5. Isothermal Titration Calorimetry-
ITC is a thermodynamic technique that
measure the heat released or absorbed
during a biomolecular binding event.
It also determination of thermodynamic
properties like –
Binding constants (KB),
reaction stoichiometry (n),
enthalpy (ΔH) & entropy (ΔS).
9. 6. MASS SPECTROMETRY-ESI-MS
NON COVALENTLY
BOUND FRAGMENT
Kd upto mM range
COVALENTLY BOUND
FRAGMENT
A French company NovAliX
They screened a fragment library of about 350 compounds against Hsp90 which resulted in 40
fragments binding to Hsp90.
7. Weak affinity chromatography-
this technique allows the detection of fragments in the 1mM to 10μM range.
10. 7. Capilarry electrophoresis- discovery for multipal compound
8. Ultrafiltration- (affinity based separation )of bound and unbound fragment The
screening resulted into 3 and 9 fragment hits for riboflavin kinase and methionine
aminopeptidase 1 respectively.
9. Biochemical assay/ high concentration screening- by this method good hit
fragment can identify , high concentration required high solubility
11. Strength and Weaknesses of Some of Commonly Used Experimental Fragment Screening Methods
Screening
method
Throughput Protein
requirement
Sensitivity Advantages Disadvantages
Ligand detected
NMR
1000s Medium-high
(µm range)
100nM-10mM High sensitive not
required labelled
protein
expensive, false
+ve rate is high,
cannot detect tight
binders
Protein detected
NMR
100s High
(50-200mg)
100nM-10mM Provided 3D
structure
information
strument is
expensive, require
isotope labeled
protein, expert
required
X-ray
crytallography
100s High
(10-50mg)
100nM-10mM Provided detail
3D structure
information
Expensive, well
diffracted high
crystal require
SPR 1000s Low
(5µg)
1nM-100mM Provide kinetic
data association
dossociation
rate,kd,kb
Protein
immobilization on
gold surface
requird
ITC 10s Low
(50-100µg)
1nM -1mM Provide high
quantitative
affinity data
Require high
sample
cocentration
MS 1000s Low
(few µg)
10nM-1mM No need protein
immobilization
Require choice of
buffer, aggregation
Biochemical assay >10000 Low
(<100µg)
Not available Simple method Reqire knowledge
of biochemical
function
12. Fragment optimization
• Fragment growing is the stepwise
addition of functional groups or
substituents to the fragment core to
maximize the favorable interactions
with the binding site residues
• The fragment linking approach is
based on covalently linking two or
more fragments bound independently
in proximity with suitable linkers.
13. CASE STUDY
1. Fragment screening against HIV -1 protease
• HIV-1 protease is a dimeric aspartic acid protease.
• Screening- consist of 384 fragment (MW142 Da) ,screening carried out
by two method
1. soaking- in that crystal p41 (pdb_id : 2PCO)
grow in the MgCl2 medium (is not compatible with DMSO)
individual crystal soaked at active site 10% DMSO, were done with C2221 crystal as
monomer
Data was collected at 7% of compound but no HIT observed.
So, another crystal form P21212,(pdb_id: 3E43) used further soaking with mix. Of 4
compound(2.5mM) ,(10 min- 1hr ) data collected of 108 crystal (17%) fragment hit
observed
2. cocrystallization- The P6122 crystal(pdb_id: 3KFP) grow and diffracted to 1.8-
2.5Å IN 10% DMSO
Containing 4 comp.at 50mM data collected containing 160 crystal at
Fig. Overview of the HIV life cycle
14. Description of hit
In fig. having two binding site , an overall hit rate of 0.8%
(1F1) ,(2F4) bind in the flap site of HIV protease, and 2-
methylcyclohexanol (4D9) binds in the exosite of HIV
protease.
Fig. A 1. Binding of 1F1 in the flap site of HIV-1 protease. B.1. Binding of 4D9 in the exosite of HIV-1 protease. A.2Fragment
binding sites on HIV-1 protease. B.2 Chemical structures of compounds for fragment screening against HIV-1 protease.
15. 2. Fragment screening against HIV-1 reverse transcriptase-
HIV-1 reverse transcriptase as a drug target.
It is a the most important drug target for HIV.
RT is a heterodimer of p66 and p51 subunits, with four polymerase subdomains.
Fig. RT-rilpivirine complex shown as a cartoon. Rilpivirine (brown space filling) is bound at
the NNRTI-binding pocket. The p66 subdomains are color-coded fingers Ordered waters are
shown as blue dots, and DMSO-d6 molecules are shown as green, yellow, and red spheres.
16. Fragment screening by SPR
• In the primary screen, 1040 fragments were screened individually for binding to
RT via SPR.
• Compound were screened at 4 concentrations from 50 to 400 mM.
• Fragments show KD value of <1 mM and stochiometries for binding of 0.75-5
times that observed for the nevirapine.
• An about 40% of the initial hits were discarded on the basis of undesirable
interaction of fragment. slow dissociation
• so, molecule it has been rejected as hit .
• After removing those fragments with undesirable SPR profiles,
• 96 compounds were selected for further experiments.
17. competition and inhibition-
• After the screening of 96 compound to select only those compound which bind on
NNRTI pocket .
• The fragment were at 200 µM and nevirapine 20µM,
• 10 compound which has been screened further, from that 2 of the fragment
found false +ve , while remaining show inhibitory activity .
• Only one fragment was found that inhibited all variants of RT tested, A, 4-bromo-
1-indanone.
18. X-ray crystallography-based fragment screening against RT:
novel druggable pockets
• HIV-1 reverse transcriptase is a
highly dynamic protein, and
• motions in the interdomain hinges
are thought to be critical to its
function.
• A fragment based screen by X-ray
crystallography against an NNRTI
inhibited RT uncovered 16 sites on
the protein that bind fragments,
several of which represent novel
druggable targets,
Fig. Fragment binding sites in reverse transcriptase.
Fragments are shown as orange spheres. Rilpivirine
is shown as yellow spheres. The p66 subunit is in
dark green and the p51 subunit in cyan. Fragment
binding sites that are described are circled.
19. Library design, soaking optimization, and data collection
Crystal RT52A rilpivirine is used for soaking, it tolerate DMSO.
Soaked in 5% ehylene glycol (for cryoprotection).
And 20% v/v DMSO 20mM for cocktail crystal(1-2 min).
No of comp,bind to RT in the presence of 80mM L-arginine.
It can also observed by trimethylamine N-oxide 6%v/v.
And improved resolution of crystal from 1.8-1.5Å
And compare the DMSO with high resolution .
Fragment binding was observed.
20. Soaking results: numerous allosteric binding sites
• The 742 fragments soaked, 34 hits were obtained, for a hit rate of 4.4%.
• These 34 compounds bound to 16 different sites of RT
21. CONCLUSION
• Fragment based drug design (FBDD) is a powerful and widely used drug
discovery approach.
• It involves the identification of low molecular weight chemical fragments and
their optimization into lead compounds.
• The generating high quality lead compounds for a variety of targets.
• The success in fragment based drug discovery use of recent technological
advancements in fragment screening technologies.
• Computational methods have already played important roles both in selecting
the initial fragments.
• Construction and deconstruction approach
• In novel drug development.
22. Recent literature
• Use of FBDD in the Discovery of Two Series of Potent Methionine Aminopeptidase-2 Inhibitors
Chris McBride, Staff Scientist, Medicinal Chemistry, Takeda
This presentation will demonstrate the strategy used to identify two series of methionine aminopeptidase-2 (MetAP2) inhibitors. Fragment libraries
were screened for hits with high ligand-efficiency (LE) and orthogonal hit confirmation led to a low affinity indazole core being selected for directed
elaboration with the aid of structural information. Additionally, structural insight and SAR from the indazole series led to the design and accelerated
knowledge-based fragment growth of the pyrazolo[4,3-b]indoles as MetAP2 inhibitors.
• FBDD on Metalloprotein Targets
Seth M. Cohen, Ph.D., Professor, Department of Chemistry and Biochemistry, University of California, San Diego
Most inhibitors of alloproteins employ a functional group that binds to the active site metal ion. We have developed an FBDD approach to
metalloenzyme inhibitors by developing a library of suitable metal-binding pharmacophores (MBPs). Thermodynamic and structural investigations
are being used to provide insight into the influence of the protein active site on MBP binding. In this presentation, our efforts on utilizing these
MBPs for metalloprotein inhibition wil
• Advances in SPR Fragment Screening
by Andrew L. Hopkins, DPhil, SULSA Research Professor, Translational Biology, University of Dundee
SPR has become the workhorse method for rapid and accurate fragment screening. We present results from a collaborative effort between the
Hopkins-Navratilova lab and GE Healthcare prototyping new assays methods and new technology to advance SPR fragment screening. We will
introduce the first results on a new, prototype Biacore™ instrument.l be discussed.
• Using Fragment- Based Lead Discovery towards Alternate Mechanisms: Inhibiting Ubiquitin Binding to USP7
Till Maurer, Ph.D., Senior Scientist, Structural Biology, Genentech
Small molecule inhibitors targeting the deubiquitinase Ubiquiti Specific Protease 7 (USP7) have potential as cancer therapeutics. Using ligand-based
NMR in an activity agnostic FBLD effort, we have identified binders to several sites in USP7 including a unique site in the “palm” of USP7. These
could be shown to be active. The palm series imply a very distinct mechanism of action independent of the catalytic triad by binding in a region
involved in USP7-Ubiquitin interaction.
23. References
• Bennett T. Farmer and Allen B. Reitz, Fragment based drug discovery, Wermuth’s The Practice of Medicinal
Chemistry, Elsevier Ltd 2008, 228-243.
• Theresa Tiefenbrunn*, C. David Stout, Towards novel therapeutics for HIV through fragment-based
screening and drug design. Published by Elsevier Ltd. Progress in Biophysics and Molecular Biology 116
(2014) 124e140, 2014.
• Christopher W Murray1 and Tom L Blundell2, Structural biology in fragment-based drug design,
www.sciencedirect.com,Current Opinion in Structural Biology 2010, 20:497–507.
• A. Kumar, A. Voet and K.Y.J. Zhang* Fragment Based Drug Design: From Experimental to Computational
Approaches, Bentham Science Publishers, Current Medicinal Chemistry, 2012, 19, 5128-5147.
• James Lanter, Xuqing Zhang, and Zhihua Sui, Medicinal Chemistry Inspired Fragment-Based Drug
Discovery, Methods in Enzymology, Volume 493, 2011 Elsevier Inc.
• Renee L. DesJarlais Contents, Using Computational Techniques in Fragment-Based Drug Discovery,
Methods in Enzymology, Volume 493, 2011 Elsevier Inc.
• Jianguo Li a,b,g, Shouping Liu a,g, Jun-Jie Koh a,e, Hanxun Zoua, Rajamani Lakshminarayanan a, Yang Bai
a,c, 4 Konstantin Pervushin c, Lei Zhou a, Chandra Verma a,b,c,d, RogerW. Beuerman a,e,f,g, A novel
fragment based strategy for membrane active antimicrobials 2 against MRSA, Published by Elsevier B.V.,
Biochimica et Biophysica Acta xxx (2015) xxx–xxx
• http:// practicalfragments. blogspot.com
• http://fbdd-lit.blogspot.com