This document discusses structure-based drug design. It begins by explaining that structure-based drug design relies on knowledge of the three-dimensional structure of biological targets, usually determined through methods like X-ray crystallography. The structure of the target is then used to design ligands that will bind to the target. The process involves identifying drug targets, determining the target's structure, performing computer-aided drug design to identify potential binding ligands, and building or modifying ligands to optimize binding to the target.
PRESENTED BY: HARSHPAL SINGH WAHI, SHIKHA D. POPALI
USEFUL FOR PHARMACY STUDENTS AND ACADEMICS, INDUSTRIALS FOR MOLECULE DEVELOPMENT, MODELING, DRUG DISCOVERY, COMPUTATIONAL TOOLS, MOLECULAR DOCKING ITS TYPES, FACTORS AFFECTING, DIFFERENT STAGES, QSAR ADVANTAGES, NEED
PRESENTED BY: HARSHPAL SINGH WAHI, SHIKHA D. POPALI
USEFUL FOR PHARMACY STUDENTS AND ACADEMICS, INDUSTRIALS FOR MOLECULE DEVELOPMENT, MODELING, DRUG DISCOVERY, COMPUTATIONAL TOOLS, MOLECULAR DOCKING ITS TYPES, FACTORS AFFECTING, DIFFERENT STAGES, QSAR ADVANTAGES, NEED
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.
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
Drug discovery take years to decade for discovering a new drug and very costly
Effort to cut down the research timeline and cost by reducing wet-lab experiment use computer modeling
Others have done the work. Some have used the work. I have spoken only on behalf of their behalf.
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.
In this slide I presented the Computer Aided Drug Design and its type :
1.Structure based Drug Design
2. Ligand based Drug Design and its Applications.
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.
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
Drug discovery take years to decade for discovering a new drug and very costly
Effort to cut down the research timeline and cost by reducing wet-lab experiment use computer modeling
Others have done the work. Some have used the work. I have spoken only on behalf of their behalf.
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.
In this slide I presented the Computer Aided Drug Design and its type :
1.Structure based Drug Design
2. Ligand based Drug Design and its Applications.
Computer Added Drug Design is one of the latest technology of medicine world. This short slide will help you to know a little about CADD.If you want to know a vast plz go throw the reference book.
B. PHARM 6TH SEMESTER DRUG DESIGN. FACTORS, QSAR, DRUG DISCOVERY, DRUG DEVELOPMENT, VARIOUS APPROACHES FOR DRUG DESIGN, PARTITION COEFFICIENT, HAMMETS EQUATION, TAFTS STERIC PARAMETER, HANSCH ANALYSIS
The techniques of drug designing and in silico studies are well defines in this presentation. Mooreover, the various softwares which are used in new era for determining the drug targets inside the body are elaborated.
This is a presentation by Dada Robert in a Your Skill Boost masterclass organised by the Excellence Foundation for South Sudan (EFSS) on Saturday, the 25th and Sunday, the 26th of May 2024.
He discussed the concept of quality improvement, emphasizing its applicability to various aspects of life, including personal, project, and program improvements. He defined quality as doing the right thing at the right time in the right way to achieve the best possible results and discussed the concept of the "gap" between what we know and what we do, and how this gap represents the areas we need to improve. He explained the scientific approach to quality improvement, which involves systematic performance analysis, testing and learning, and implementing change ideas. He also highlighted the importance of client focus and a team approach to quality improvement.
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.
The Roman Empire A Historical Colossus.pdfkaushalkr1407
The Roman Empire, a vast and enduring power, stands as one of history's most remarkable civilizations, leaving an indelible imprint on the world. It emerged from the Roman Republic, transitioning into an imperial powerhouse under the leadership of Augustus Caesar in 27 BCE. This transformation marked the beginning of an era defined by unprecedented territorial expansion, architectural marvels, and profound cultural influence.
The empire's roots lie in the city of Rome, founded, according to legend, by Romulus in 753 BCE. Over centuries, Rome evolved from a small settlement to a formidable republic, characterized by a complex political system with elected officials and checks on power. However, internal strife, class conflicts, and military ambitions paved the way for the end of the Republic. Julius Caesar’s dictatorship and subsequent assassination in 44 BCE created a power vacuum, leading to a civil war. Octavian, later Augustus, emerged victorious, heralding the Roman Empire’s birth.
Under Augustus, the empire experienced the Pax Romana, a 200-year period of relative peace and stability. Augustus reformed the military, established efficient administrative systems, and initiated grand construction projects. The empire's borders expanded, encompassing territories from Britain to Egypt and from Spain to the Euphrates. Roman legions, renowned for their discipline and engineering prowess, secured and maintained these vast territories, building roads, fortifications, and cities that facilitated control and integration.
The Roman Empire’s society was hierarchical, with a rigid class system. At the top were the patricians, wealthy elites who held significant political power. Below them were the plebeians, free citizens with limited political influence, and the vast numbers of slaves who formed the backbone of the economy. The family unit was central, governed by the paterfamilias, the male head who held absolute authority.
Culturally, the Romans were eclectic, absorbing and adapting elements from the civilizations they encountered, particularly the Greeks. Roman art, literature, and philosophy reflected this synthesis, creating a rich cultural tapestry. Latin, the Roman language, became the lingua franca of the Western world, influencing numerous modern languages.
Roman architecture and engineering achievements were monumental. They perfected the arch, vault, and dome, constructing enduring structures like the Colosseum, Pantheon, and aqueducts. These engineering marvels not only showcased Roman ingenuity but also served practical purposes, from public entertainment to water supply.
We all have good and bad thoughts from time to time and situation to situation. We are bombarded daily with spiraling thoughts(both negative and positive) creating all-consuming feel , making us difficult to manage with associated suffering. Good thoughts are like our Mob Signal (Positive thought) amidst noise(negative thought) in the atmosphere. Negative thoughts like noise outweigh positive thoughts. These thoughts often create unwanted confusion, trouble, stress and frustration in our mind as well as chaos in our physical world. Negative thoughts are also known as “distorted thinking”.
Read| The latest issue of The Challenger is here! We are thrilled to announce that our school paper has qualified for the NATIONAL SCHOOLS PRESS CONFERENCE (NSPC) 2024. Thank you for your unwavering support and trust. Dive into the stories that made us stand out!
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.
Instructions for Submissions thorugh G- Classroom.pptxJheel Barad
This presentation provides a briefing on how to upload submissions and documents in Google Classroom. It was prepared as part of an orientation for new Sainik School in-service teacher trainees. As a training officer, my goal is to ensure that you are comfortable and proficient with this essential tool for managing assignments and fostering student engagement.
2. Content
Abstract
Drug
Aims and Objective
Drug design
Drug design Approaches
Basic principle
Challenges of drug design
Types of drug design
Structure base drug design
Structure base drug design process
Conclusion
3.
4. DRUG-
Drug are small molecules design to bind, interact,and modulate the activity of specific
biological receptors.
Receptors are proteins that bind and interact with other molecules to perform the
numerous functions required for the maintenance of life.
The role of drugs is to correct the functioning of these receptors to remedy the resulting
medical condition.
5. STRUCTURAL FRAGMENTS OF A DRUG
MOLECULE: Pharmacophore
The three-dimensional arrangement of atoms within a drug molecule that permits a
specific binding interaction with a desired receptor is called Pharmacophore.
The pharmacophore is the bioactive face of the molecule and is that portion of the
molecule that establishes intermolecular interactions with the receptor site .
6. we see our native ligand bound within the active site.
Assume that through biochemical investigation, we determine that the phenyl ring (blue)
and the carboxylic acid group (green) are vital to receptor interaction.
Thus, we deduce that these two groups must be the pharmacophore that a ligand must
present to the receptor for binding.
This is shown in the upper right derivative compound where a bicyclic group has been
substituted. Because it maintains the pharmacophore and retains its complementary size
and shape, it has a reasonable chance of successfully binding.
However, any drug that we develop which lacks a complete pharmacophore may not
interact with the receptor target.
7. Aims & Objectives:-
The central aim of the course is to impart an understanding of what medicinal chemists
have to think about when attempting to design new drugs.
To understand how to relate chemical structure to biological activity.
To understand how to conduct a structure-activity analysis.
Identify at least one small molecule with improved activity over existing drugs with the
same target.
Submit some of the molecules produced for pharmaceutical testing
8. Drug design
Drug design, sometimes referred to as rational drug design or
more simply rational design, is the inventive process of
finding new medications based on the knowledge of a
biological target..
9. DRUG DESIGN APPROACHSDRUG DESIGN APPROACHS
A CONCEPTUAL APPROACHA CONCEPTUAL APPROACH
Drug design may be divided into two phasesDrug design may be divided into two phases..
1)1) Basic concepts about drug,receptors,and drug- receptor interaction.Basic concepts about drug,receptors,and drug- receptor interaction.
2)2) Basic concepts about drug-receptor interactions applied to human disease.Basic concepts about drug-receptor interactions applied to human disease.
First phaseFirst phase
comprises the essential building blocks of drug design and may be divided intocomprises the essential building blocks of drug design and may be divided into
three logical steps:three logical steps:
10. Step1-
Involves knowing what property turn a molecule into a drug.
All drugs may be molecules, but all molecules are certainly not drugs.
Drug molecules are “small”organic molecules (molecular weight usually below
800g/mol. Often below 500).eg ;Penicillin, acetylsalicyclic acid,and morphine are
all small orrganic molecules.
11. Step II-
Involves knowing what propertes turn a macromolecule into a receptor.
All receptors may be macromolecules, but all macromolecules are certainly not
receptors.
Receptor macromolecules are frequently proteins or glycoprotein's.
Step III-Step III-
Involves knowing how to design and synthesize a drug to fit into a receptorInvolves knowing how to design and synthesize a drug to fit into a receptor
This prototype compound is referred to as the lead compound.This prototype compound is referred to as the lead compound.
12. Second phase-
Once the basics of drug design are in place,the drug designer next focuses upon the task
of connecting a drug-receptor interaction to a human disease- this is the goal of the second
phase.
This phase of drug design requires an understanding of biochemistry and of the molecular
pathology of the disease being treated.
13. DRUG DESIGN :A PRACTICALAPPROACH
This strategy uses a molecular-level understanding of human biochemistry and pathology
to drive the design of drug .
Drug like molecules engineered to fit precisely into targets of drug action (druggable
targets)
14. DRUG DESIGN :THE HUMANITARIANDRUG DESIGN :THE HUMANITARIAN
APPROCHAPPROCH
In traditional medicine there are two major therapeutic approaches to the
treatment of human disease:
a) Surgical procedures are labour intensive and time demanding; they help a limit
number of individuals,one at a time, mostly in rich or developed nations.
b) Medical therapeutics offer hope in both developed and developing parts of the
world-hopefully to rich and poor alike
15. Basic Principles of Drug DesignBasic Principles of Drug Design
• Medicinal chemistry is the applied science that is focused on the design of new
chemical entities (NCEs) and their optimization and development as useful drug
molecule for the treatment of disease processes.
• In achieving this mandate, the medicinal chemist must design and synthesize new
molecules,ascertain how they interact with biological macromolecules (such as
proteins or nucleic acids),elucidate the relationship between their structure and
biological activities,determine their absorption and distribution throughout the
body ,and evaluate their metabolic transformations.
16. The challenges of drug design
We can begin to appreciate the difficulties in designing drugs towards specific target
receptors.
Major tasks and concerns in drug development
Achieve active site complementary:
Consider biochemical mechanism of receptor
Adhere to laws of chemistry.
Synthetic feasibility
Biological considerations
Patent considerations
Characterize medical condition and determine receptor targets .
The pharmacophore must be presented to the receptor in order for recognition and
binding to occur. Otherwise, the designed ligand will have no chance of
interacting with the receptor.
17. TYPES OF DRUG DESIGN
Ligand based drug design:
Ligand-based drug design (or indirect drug design) relies on knowledge of other
molecules that bind to the biological target of interest.
These other molecules may be used to derive a pharmacophore model that defines the
minimum necessary structural characteristics a molecule must possess in order to bind to
the target.
Alternatively, a quantitative structure-activity relationship (QSAR), in which a
correlation between calculated properties of molecules and their experimentally
determined biological activity, may be derived.
These QSAR relationships in turn may be used to predict the activity of new analogs.
18. Rational drug discovery
Rational drug design begins with a hypothesis that modulation of a specific
biological target may have therapeutic value.
In order for a biomolecule to be selected as a drug target, two essential pieces of
information are required.
The first is evidence that modulation of the target will have therapeutic value.
This knowledge may come from, for example, disease linkage studies that show an
association between mutations in the biological target and certain disease states.
The second is that the target is "drugable". This means that it is capable of binding
to a small molecule and that its activity can be modulated by the small molecule.
19. Computer-aided drug design
Computer-aided drug design uses computational chemistry to discover, enhance, or
study drugs and related biologically active molecules.
The most fundamental goal is to predict whether a given molecule will bind to a target
and if so how strongly
Ideally the computational method should be able to predict affinity before a compound
is synthesized and hence in theory only one compound needs to be synthesized.
20. Structure Base Drug Design
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 or NMR spectroscopy.
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.
Using the structure of the biological target,In parallel, information about the structural
dynamics and electronic properties about ligands has also increased. This has
encouraged the rapid development of the structure-based drug design.
21. Current methods for structure-based drug design can be
divided roughly into two categories.
a) The first category is about “finding” ligands for a given receptor, which is
usually referred as database searching.The key advantage of database
searching is that it saves synthetic effort to obtain new lead compounds.
b) Another category of structure-based drug design methods is about
“building”ligands, which is usually referred as receptor-based drug design.
The key advantage of such a method is that novel structures, not contained in
any database, can be suggested.
23. Structure Base Drug design process
Fig:6 structure base drug design process
24. Target identification
The choice of a drug target is primarily made on a biological and biochemical basis.
The ideal target macromolecule for structure-based drug design is one that is closely
linked to human disease and binds a small molecule in order to carry out a function.
The target should be unique
Practices such as systems biology, clustering, and drug affinity response have
matured to help with the identification of biological targets
Homology modeling or comparative modeling is the most reliable method for target
structure prediction that builds 3D structures for unknown proteins based on the
known homologous protein structures (i.e. >40% similarity)
25. Evaluating of identified target
Once a target has been identified, it is necessary to obtain accurate structural
information.
There are three primary methods for structure determination that are useful for drug
design:X-ray crystallography, NMR, and homology modeling.
Crystal structures are the most common source of structural information for drug
design, since structures determined to high resolution may be available, and the
method is useful for proteins that range in size from a few amino acid.
26. Target validation
The binding site is a small region, a pocket or bumps, where ligand molecules can best fit
or bind to activate the receptor and/or target and produce the desirable effect.
Thus, recognizing the binding site or the active site residues in the target structure is of
high importance in SBDD. Because the proteins are capable of undergoing conformational
changes, recognizing the accurate binding site residues is difficult
It is an accepted fact that proper selection of chemical compounds, with minimal potency
and specificity, during the early phases of drug discovery plays a vital part in the success
Structure-based design begins with the identification of a potential ligand binding site on
the target molecule.
27. Lead Drug Evaluation
Once a small molecule has been identified as potentially binding to the target molecule, it
must be evaluated before proceeding to further stages.
It is important to consider that the ranking assigned by the scoring function is not always
indicative of a true binding constant, since the model of the target:ligand interaction is
inherently an approximation.
Usually, several molecules which scored well during the docking run are evaluated in further
tests since even the top scoring molecule could fail in vitro assays.
Leads are first evaluated visually with computer graphics and can often be optimized at this
step for increased affinity.
Leads are also evaluated for their likelihood to be orally bioavailable which states that good
leads generally have less than five hydrogen bond donors and less than ten hydrogen bond
acceptors, a molecular weight less than 500, and a calculated log of the partition coefficien
less than 5
28. Lead Optimization:-Various approaches are employed in order to improve
the desired pharmacological properties of the lead nucleus.
Identification of active part(the pharmaco-phore)
Any drug molecule consists of both, essential and nonessential parts.
Essential part is important in governing pharmacodynamic (drug-receptor
interaction ) property
while Non-essential part influences pharmacokinetic features.Once such
pharmacophore is identified,structural modification can be done to improve
pharmacokinetic properties of the drug
Functional group optimization
The activity of a drug can be correlated to its structure in terms of the
contribution of its functional groups to the lipophilicity, electronic and steric
features of the drug skeleton..
Structure activity relationship studies:-
SAR studies usually involve the interpretation of activity in terms of the
structural features of a drug molecule.
Generalized conclusions then can be made after examining a sufficient number of
drug analogs for example, sulphonamides are found to be associated with diuretic
and antidiabetic activities in addition to their antibacterial activity.
29. Homologation:
A homologous series is a group of compounds that differ by a constant unit,
generally a CH2 group.
Usually increasing the length of a saturated carbon side-chain from one (CH3) to 5 to
9 atoms produces an increase in pharmacological effects.
Further increase results in a decrease in the activity.
This is probably either due to increase in lipophilicity beyond optimum value (hence
decreased absorption and distribution) or decrease in concentration of free drug (i.e.,
micelle formation).
For example, maximum hypnotic activity is seen from 1-hexanol to 1-octanol.
Cyclization of the side –Chain :
Change in the potency or change in the activity spectra can be brought about by
transformation of alkyl side chain into cyclic analogs.
30. DOCKING-
The aim of molecular docking is to find the “best” match between a putative ligand and
a target with known structure by placing a molecule into the binding site of the target
in a non-covalent fashion.
There are three baasic tsks:
1) Characterization of the binding site;
2) Positioning of the ligand into the binding site
3) Evaluating the strength of interaction for a specific receptor-ligand complex (scoring).
Docking a process of predicting the ligand conformation and its orientation inside the
target structure, plays a vital part in SBDD
31. Structural based design: Docking
Induced fit docking
Lock and Key
+
Substrate
(ligand)
Enzyme
(receptor) +Substrate
(ligand)
Enzyme
(receptor)
Induced Fit
32. Conclusion
Thus, it can be said that pharmaceutical and biotechnology research has undergone great change.
Traditionally, the crucial impasse in the industry's search for new drug targets was the availability of
biological data.
Now with the advent of human genomic sequence, bioinformatics offers several approaches for the
prediction of structure and function of proteins on the basis of sequence and structural similarities.
The protein sequence→structure→function relationship is well established and reveals that the
structural details at atomic level help understand molecular function of proteins.
Impressive technological advances in areas such as structural characterization of biomacromolecules,
computer sciences and molecular biology have made rational drug design feasible and present a
holistic approach
The approaches and methodologies used in drug design have changed over time, In addition to the
experimental techniques, a variety of computational approaches have been applied at the various
stages of the drug-design process: in the early stages these approaches focused on reducing the
number of possible ligands, whereas in the later stages, during lead-optimization, the emphasis is on
decreasing experimental costs and reducing the period of discovery.
33. References:-
Shen H, Wang F, Zhang Y, Huang Q, Xu S, Hu H, et al. A novel inhibitor of
indole-3-glycerol phosphate syntheses with activity against multi drug-
resistant Mycobacterium tuberculosis. FEBS J 2009; 276:144-54.
DRUG DESIGN ,Dr.V.M. KULKARNI,Dr.K.G.BOTHARA,NIRALI
PRAKASHAN Pg.No.-6-10
Wang R,Gao Y,Lai L (2000). "LigBuilder: A Multi-Purpose Program for
Structure Based Drug Design". Journal of Molecular Modeling 6 (7–8):
498–516.
Medicinal Chemistry A Molecular and biochemical Approache 3rd
Edition,Thomas Nogrdy,Donald F.Weaver Pg.no. 5-9,19
wikipedia the free encyclopedia
http://en wikipedia.org/wki/drug design#cite-note-CBDDreview-6#
http://www.newdrugdesign.com/Rachel-Theory-13 html