This document discusses the importance of conformational isomers or rotamers in drug molecules. It explains that while molecules can exist in infinite conformations due to free rotation around single bonds, not all conformations are equally stable. The preferred conformation minimizes repulsive interactions and maximizes attractive interactions. The active conformation that binds to a receptor may be different from the preferred conformation. Conformational restriction techniques like double bond introduction or ring closure can be used to lock molecules in a desired bioactive conformation. Understanding conformational analysis is important for drug design and determining molecular activity.
stereochemistry and drug action ; basic introduction about stereochemistry and stereoisomers ; pharmacokinetic and pharmacodynamics concept of stereochemistry ; easson Stedman hypothesis ; stereo selectivity criteria .
stereochemistry and drug action ; basic introduction about stereochemistry and stereoisomers ; pharmacokinetic and pharmacodynamics concept of stereochemistry ; easson Stedman hypothesis ; stereo selectivity criteria .
1. Receptors
2. Receptor dynamics
3. Drug receptor binding
4. Agonists & Types of Agonists
5. Antagonists
6. Constants related to antagonists
7. Types of antagonists
8. Mechanisms of actions of receptors
9. Thank you
Analog design is usually defined as the modification of a drug molecule or of any bioactive compound in order to prepare a new molecule showing chemical and biological similarity with the original model compound
Recent Structure Activity Relationship Studies of 1,4-Benzodiazepinespeertechzpublication
Structure activity relationship studies of 1,4-benzodiazepines have been discussed especially
with their effects as antianxiety and anticonvulsants. The currently available benzodiazepines are
associated with various side effects. Nowadays the purpose of these studies is to minimize side effects
with these drugs. A very little alteration is possible on the benzene ring while the modification can be
done on the diazepine ring. It can adopt the different conformations and in some cases some aromatic
and heterocyclic rings have been fused with this part in order to see the effect of these conformation
blockers on the pharmacological activity. The structure activity studies are also linked to molecular
modeling studies. This is important in adding some information for the interaction of these drugs with
the receptors and how this interaction can be improved.
Receptor types, mechanism, receptor pharmacology, drug receptor interactions, theories of receptor pharmacology, spare receptors and new concepts like biased agonism
Proteins are dynamic molecules whose functions almost invariably depend on interactions with other molecules.
A molecule bound reversibly by a protein is called a ligand.
A ligand binds at a site on the protein called the binding site, which is complementary to the ligand in size, shape, charge, and hydrophobic or hydrophilic character.
Introduction
Examples of Protein-Ligand interactions
Protein-Ligand Interactions Can Be Described Quantitatively
Cooperative Ligand Binding Can Be Described Quantitatively by Hill Equation
Physical and chemical methods of protein-ligand interaction study
Verification of interactions
Public protein–protein interaction databases
Ligand docking
Conclusions
References
1. Receptors
2. Receptor dynamics
3. Drug receptor binding
4. Agonists & Types of Agonists
5. Antagonists
6. Constants related to antagonists
7. Types of antagonists
8. Mechanisms of actions of receptors
9. Thank you
Analog design is usually defined as the modification of a drug molecule or of any bioactive compound in order to prepare a new molecule showing chemical and biological similarity with the original model compound
Recent Structure Activity Relationship Studies of 1,4-Benzodiazepinespeertechzpublication
Structure activity relationship studies of 1,4-benzodiazepines have been discussed especially
with their effects as antianxiety and anticonvulsants. The currently available benzodiazepines are
associated with various side effects. Nowadays the purpose of these studies is to minimize side effects
with these drugs. A very little alteration is possible on the benzene ring while the modification can be
done on the diazepine ring. It can adopt the different conformations and in some cases some aromatic
and heterocyclic rings have been fused with this part in order to see the effect of these conformation
blockers on the pharmacological activity. The structure activity studies are also linked to molecular
modeling studies. This is important in adding some information for the interaction of these drugs with
the receptors and how this interaction can be improved.
Receptor types, mechanism, receptor pharmacology, drug receptor interactions, theories of receptor pharmacology, spare receptors and new concepts like biased agonism
Proteins are dynamic molecules whose functions almost invariably depend on interactions with other molecules.
A molecule bound reversibly by a protein is called a ligand.
A ligand binds at a site on the protein called the binding site, which is complementary to the ligand in size, shape, charge, and hydrophobic or hydrophilic character.
Introduction
Examples of Protein-Ligand interactions
Protein-Ligand Interactions Can Be Described Quantitatively
Cooperative Ligand Binding Can Be Described Quantitatively by Hill Equation
Physical and chemical methods of protein-ligand interaction study
Verification of interactions
Public protein–protein interaction databases
Ligand docking
Conclusions
References
Advanced Medicinal Chemistry of GPCR Receptorsaurabh gupta
Contents:-
Introduction
Structure of G-protein
Signal Molecules / Ligands of GPCRs
G- Protein Mediated Pathways
Receptor Site Theories
Forces involved in drug receptor interactions
FUNCTIONAL GROUP MODIFICATION : Medicinal ChemistryPRUTHVIRAJ K
Once a lead compound or a pharmacophore structure with the desired pharmacological effect has been identified, organic chemists can introduce modifications in the chemical structure of the lead compound with the goal of improving the pharmacokinetics or pharmacodynamics of a drug candidate. These evolved structures are known as analogs.
3
POLYMERS IN SOLID STATE, PHARMACEUTICAL APPLICATIONS OF POLYMERS AND RECENT A...Priyanka Modugu
A description on polymers in solid state, solid state properties of polymers, mechanical properties of polymers, heat of crystallization & fusion, thermodynamics of fusion & crystallization, pharmaceutical applications of polymers and recent advances in the use of polymers for drug delivery system
Introduction:
RNA interference (RNAi) or Post-Transcriptional Gene Silencing (PTGS) is an important biological process for modulating eukaryotic gene expression.
It is highly conserved process of posttranscriptional gene silencing by which double stranded RNA (dsRNA) causes sequence-specific degradation of mRNA sequences.
dsRNA-induced gene silencing (RNAi) is reported in a wide range of eukaryotes ranging from worms, insects, mammals and plants.
This process mediates resistance to both endogenous parasitic and exogenous pathogenic nucleic acids, and regulates the expression of protein-coding genes.
What are small ncRNAs?
micro RNA (miRNA)
short interfering RNA (siRNA)
Properties of small non-coding RNA:
Involved in silencing mRNA transcripts.
Called “small” because they are usually only about 21-24 nucleotides long.
Synthesized by first cutting up longer precursor sequences (like the 61nt one that Lee discovered).
Silence an mRNA by base pairing with some sequence on the mRNA.
Discovery of siRNA?
The first small RNA:
In 1993 Rosalind Lee (Victor Ambros lab) was studying a non- coding gene in C. elegans, lin-4, that was involved in silencing of another gene, lin-14, at the appropriate time in the
development of the worm C. elegans.
Two small transcripts of lin-4 (22nt and 61nt) were found to be complementary to a sequence in the 3' UTR of lin-14.
Because lin-4 encoded no protein, she deduced that it must be these transcripts that are causing the silencing by RNA-RNA interactions.
Types of RNAi ( non coding RNA)
MiRNA
Length (23-25 nt)
Trans acting
Binds with target MRNA in mismatch
Translation inhibition
Si RNA
Length 21 nt.
Cis acting
Bind with target Mrna in perfect complementary sequence
Piwi-RNA
Length ; 25 to 36 nt.
Expressed in Germ Cells
Regulates trnasposomes activity
MECHANISM OF RNAI:
First the double-stranded RNA teams up with a protein complex named Dicer, which cuts the long RNA into short pieces.
Then another protein complex called RISC (RNA-induced silencing complex) discards one of the two RNA strands.
The RISC-docked, single-stranded RNA then pairs with the homologous mRNA and destroys it.
THE RISC COMPLEX:
RISC is large(>500kD) RNA multi- protein Binding complex which triggers MRNA degradation in response to MRNA
Unwinding of double stranded Si RNA by ATP independent Helicase
Active component of RISC is Ago proteins( ENDONUCLEASE) which cleave target MRNA.
DICER: endonuclease (RNase Family III)
Argonaute: Central Component of the RNA-Induced Silencing Complex (RISC)
One strand of the dsRNA produced by Dicer is retained in the RISC complex in association with Argonaute
ARGONAUTE PROTEIN :
1.PAZ(PIWI/Argonaute/ Zwille)- Recognition of target MRNA
2.PIWI (p-element induced wimpy Testis)- breaks Phosphodiester bond of mRNA.)RNAse H activity.
MiRNA:
The Double-stranded RNAs are naturally produced in eukaryotic cells during development, and they have a key role in regulating gene expression .
The increased availability of biomedical data, particularly in the public domain, offers the opportunity to better understand human health and to develop effective therapeutics for a wide range of unmet medical needs. However, data scientists remain stymied by the fact that data remain hard to find and to productively reuse because data and their metadata i) are wholly inaccessible, ii) are in non-standard or incompatible representations, iii) do not conform to community standards, and iv) have unclear or highly restricted terms and conditions that preclude legitimate reuse. These limitations require a rethink on data can be made machine and AI-ready - the key motivation behind the FAIR Guiding Principles. Concurrently, while recent efforts have explored the use of deep learning to fuse disparate data into predictive models for a wide range of biomedical applications, these models often fail even when the correct answer is already known, and fail to explain individual predictions in terms that data scientists can appreciate. These limitations suggest that new methods to produce practical artificial intelligence are still needed.
In this talk, I will discuss our work in (1) building an integrative knowledge infrastructure to prepare FAIR and "AI-ready" data and services along with (2) neurosymbolic AI methods to improve the quality of predictions and to generate plausible explanations. Attention is given to standards, platforms, and methods to wrangle knowledge into simple, but effective semantic and latent representations, and to make these available into standards-compliant and discoverable interfaces that can be used in model building, validation, and explanation. Our work, and those of others in the field, creates a baseline for building trustworthy and easy to deploy AI models in biomedicine.
Bio
Dr. Michel Dumontier is the Distinguished Professor of Data Science at Maastricht University, founder and executive director of the Institute of Data Science, and co-founder of the FAIR (Findable, Accessible, Interoperable and Reusable) data principles. His research explores socio-technological approaches for responsible discovery science, which includes collaborative multi-modal knowledge graphs, privacy-preserving distributed data mining, and AI methods for drug discovery and personalized medicine. His work is supported through the Dutch National Research Agenda, the Netherlands Organisation for Scientific Research, Horizon Europe, the European Open Science Cloud, the US National Institutes of Health, and a Marie-Curie Innovative Training Network. He is the editor-in-chief for the journal Data Science and is internationally recognized for his contributions in bioinformatics, biomedical informatics, and semantic technologies including ontologies and linked data.
THE IMPORTANCE OF MARTIAN ATMOSPHERE SAMPLE RETURN.Sérgio Sacani
The return of a sample of near-surface atmosphere from Mars would facilitate answers to several first-order science questions surrounding the formation and evolution of the planet. One of the important aspects of terrestrial planet formation in general is the role that primary atmospheres played in influencing the chemistry and structure of the planets and their antecedents. Studies of the martian atmosphere can be used to investigate the role of a primary atmosphere in its history. Atmosphere samples would also inform our understanding of the near-surface chemistry of the planet, and ultimately the prospects for life. High-precision isotopic analyses of constituent gases are needed to address these questions, requiring that the analyses are made on returned samples rather than in situ.
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...Sérgio Sacani
Since volcanic activity was first discovered on Io from Voyager images in 1979, changes
on Io’s surface have been monitored from both spacecraft and ground-based telescopes.
Here, we present the highest spatial resolution images of Io ever obtained from a groundbased telescope. These images, acquired by the SHARK-VIS instrument on the Large
Binocular Telescope, show evidence of a major resurfacing event on Io’s trailing hemisphere. When compared to the most recent spacecraft images, the SHARK-VIS images
show that a plume deposit from a powerful eruption at Pillan Patera has covered part
of the long-lived Pele plume deposit. Although this type of resurfacing event may be common on Io, few have been detected due to the rarity of spacecraft visits and the previously low spatial resolution available from Earth-based telescopes. The SHARK-VIS instrument ushers in a new era of high resolution imaging of Io’s surface using adaptive
optics at visible wavelengths.
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
Seminar of U.V. Spectroscopy by SAMIR PANDASAMIR PANDA
Spectroscopy is a branch of science dealing the study of interaction of electromagnetic radiation with matter.
Ultraviolet-visible spectroscopy refers to absorption spectroscopy or reflect spectroscopy in the UV-VIS spectral region.
Ultraviolet-visible spectroscopy is an analytical method that can measure the amount of light received by the analyte.
2. IT MAY INCREASE OR DECREASE THE
POTENCY OF THE DRUG.
IT MAY GIVE UNTOWARD SIDE EFFECTS
EVEN RIGIDITY OR FLEXIBILITY OF THE
STRUCTURE COUNTS A LOT DURING
DRUG RECEPTOR INTERACTIONS.
4. IT SHOULD POSSESS A SINGLE BOND and
shouldnot be present in the ring system.
Neither of the atoms which are joined by this
single bond can contain three identical
substituents (e.g., three hydrogen atoms, three
methyl groups, etc.) or else rotation about the
bond will be irrevelant.
Bound to a nonterminal heavy atom Excluded
from the count are amide C–N bonds because
of their high rotational energy barrier .
8. IMAGINE A DRUG
MOLECULE LIKE
ACETYLCHOLINE
HERE THE
ROTATIONS IS
POSSIBLE BETWEEN 4
AND 5.
TRANS CONFORMER
IS THE MOST STABLE
CONFORMER .
9. KNOW THE DIFFERENCE BETWEEN A
PREFERRED CONFORMATIONS AND
ACTIVE CONFORMATIONS
ADVANTAGES AND DISADVANTAGES OF
CONFORMATIONAL RESTRICTIONS.
10. •THOUGH INFINITE CONFORMERS ARE
POSSIBLE DUE TO FREE ROTATION AROUND
A SINGLE BOND.
•ALL CONFORMERS ARE NOT OF EQUAL
IMPORTANCE.
•IN 1936,KEMP AND PITZER DETERMINED
THAT
• ROTATIONS OF THE CONFORMER ARE DUE
TO SOME ENERGY BARRIER
11. •STERIC REPULSION
•ELECTRONIC INTERACTIONS AMONG THE GROUPS.
Conformations which minimize any repulsive
interactions and maximize all attractive interactions
are more energetically favorable than other conformations
and are said to be PREFERRED CONFORMATIONS.
12. Hence for acyclic compounds conformations where the
larger groups are staggered and separated by greater
distance are more energetically favorable than skew
conformer.
13. IF FORCE OF ATTRACTION COMPENSATE STERIC
REPULSION FOR EXAMPLE
Gauche Conformer is the most stable one due to
intramolecular hydrogen bonding.
14. LOOKING INTO THE STERIC CONCEPT IT CAN BE THE STAGGERED
ONE BUT BY SPECTROGRAPHIC ANALYSIS IT IS THE GAUCHE FORM
WHICH IS PREFERRED.
•DUE TO INTRAMOLECULAR ATTRACTION BETWEEN
QUATERNARY NITROGEN AND ESTER CARBONYL
OVERCOMES THE STERIC BARRIER AND STABILIZES IT.
16. DRUG MOLECULE CONFORMER THAT
BINDS TO A RECEPTOR OR AN ENZYME.
IT CONTAINS THE CORRECT SPATIAL
ARRANGEMENTS OF ALL ESSENTIAL
GROUPS REQUIRED FOR
PHARMACOLOGICAL EFFECT
IT MAY NOT BE THE PREFERRED ONE.
17. •IN ACETYLCHOLINE GAUCHE MAY BE THE PREFERRED ONE BUT
TRANS CONFORMER IS USED FOR BINDING WITH MUSCARINIC
RECEPTOR .
•IN TACROLIMUS IT MUST UNDERGO CIS-TRANS ISOMERIZATION OF
THE AMIDE BOND TO BIND TO THE RECEPTOR.
•CYCLOSPORINE IS TURNED INSIDE OUT TO GET ACTIVE BOUND
CONFORMATION LIKE ITS PEPTIDE BOND ISOMERIZES FROM CIS TO
TRANS.
ABOVE EXAMPLES SHOWS
THAT DRUGS SHOULD BE
FLEXIBLE FOR BINDING TO
DRUG RECEPTORS .
18. ACTIVE CONFORMATIONS BINDS TO THE
RECEPTORS WITH IDEAS LIKE
INDUCED FIT THEORY OR ZIPPER
MECHANISM OF BINDING DRUGS.
IN INDUCED FIT THEORY BY KOSHLAND
STATES THAT THERE IS A CHANGE IN THE
CONFORMATIONS OF THE RECEPTORS
FOR EFFECTIVE BINDING AND TO
PRODUCE A BIOLOGICAL RESPONSE.
IT IS A DYNAMIC PROCESS WITH MUTUAL
MOLDING OF BOTH RECEPTOR AND
MOLECULE.
19.
20. CONFORMATIONAL
RESTRICTION
LOCK A MOLECULE IN
DESIRED
CONFORMATIONS.
FOR AN EXAMPLE IF X
AND Y ARE TWO
GROUPS REQUIRED FOR
THERAPEUTIC
PURPOSE AND B AND C
ARE ACTIVE
CONFORMER THEN
RESTRICTION OF A
PARTICULAR
CONFORMATION IS
REQUIRED.
21. USED AS SPECIFIC AGONIST/ANATAGONIST FOR
RECEPTORS
IT CAN REDUCE UNECESSARY SIDE EFFECTS OF
THE DRUGS.
SINGLE DRUG MOLECULE CAN PROVIDE
DIFFERENT EFFECTS IN THEIR DISTINCT
CONFORMERS.
INCREASED DURATION OF ACTION
22. THEREFORE A CONFORMATIONALLY ACTIVE
MOLECULE WITH ALL REQUIRED GROUPS IN
PROPER ORIENTATION HAVE HIGH AFFINITY FOR
THE RECEPTORS.
23. INTRODUCTION OF A DOUBLE BOND
E.g chlorpromazine produces antipsychotic
affects by blocking dopamine receptors.
THE ACTIVE CONFORMER IS THAT IN
WHICH THE NITROGEN IS LOCATED IN THE
CHLORINE CONTAINING AROMATIC RING.
SIDECHAIN IS FLEXIBLE AND NO OF
CONFORMERS ARE POSSIBLE,
24. INTRODUCTION OF
A DOUBLE BOND
GIVES RISE TO
THIOXANTHENE
(chlorprothixene)CLASS
OF DERIVATIVES
WITH E AND Z
ISOMERS.
FURTHER THE
REQUIRED
BIOACTIVE
CONFORMER IS THE
Z ISOMER THAN E.
25. PROVIDES MORE RESTRICTION
RING CLOSURE MECHANISM TO CHANGE
ACTIVITY OF A PROFILE.
E.g AMPHETAMINE IS A POTENT CNS
STIMULANT.
TRANYLCYPROMINE IS A POTENT MAO
INHIBITOR
AFTER RING CLOSURE TRANYLCYPROMINE
IS 5000 TIMES MORE POTENT MAO
INHIBITOR THEN AMPHETAMINE.
26. Phenmetrazine is a cyclic analog of ephedrine. While
Ephedrine a conformationaly flexible molecule, is an
indirect acting adrenergic agonist with CNS stimulating
activity,phenmetrazine a conformationaly restricted
molecule, retains the activity of ephedrine without
pronounced CNS stimulation.
27. THE DIRECTION IN WHICH THE RING IS
CLOSED MAY GIVE RISE TO CIS –TRANS
ISOMER
THE EXTENT OF RESTRICTION IMPOSED
BY THE CLOSURE
28. CONFORMATIONAL ANALYSIS IS A
REQUIRED PARAMETER TO DETERMINE
THE ACTIVITY OF DRUG MOLECULES. A
BRIEF IDEA ABOUT THESE IS REQUIRED
DURING CHEMICAL DESIGN OF NEW
COMPOUNDS.
29. American Journal of Pharmaceutical
Education Vol. 60, Summer 1996
J. Pharm. Pharmac., 1967, 19, 561-589
FOYE PRINCIPLES OF MEDICINAL
CHEMISTRY
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