Combinating Drug Resistance �and Analog Design.pptx

Content:Drug resistence.
Stratergies to Combat antimicrobial resistance.
Stratergies to combat anticancer resistance.
Genetic principles of drug resistance.
Geometric isomers.
Fragments of the lead molecule.
Variation in interatomic distances.
Drug resistance:
Microbes are still grow in presence of drug
It may lead to treatment failure
Spread in a society or community. Mechanisms of Resistance Gene Transfer:Transfer of r-genes from one bacterium to another:

Conjugation:- make a connecting tube between the 2 bacteria through which plasmid itself can pass.
Transduction:-bacteriophage contain plasmid DNA is transferred to another bacterium of same species.
Transformation:-Free DNA is picked up from the environment i.e. From a cell belonging to closely related.

Transfer of r-genes between plasmids within the bacterium
By transposons
By Integrons
Transposons:
Stratergies to Combat antimicrobial resistance :
Stratergies to Combat anticancer resistance:Including surgery, radiation, nuclear therapy etc.
ATP-binding cassette (ABC) transporters:
For developing more effective therapies Identifying the mechanisms leading to intrinsic or acquired multidrug resistance (MDR) is important.
Due to expression of particular proteins results in cancer cells resistance-such as cell-membrane transporters, which can result in an increased efflux of the cytotoxic drugs from the cancer cells, thus lowering their concentrations.
When overexpression of the membrane efflux pumps is involved in MDR .
The resistance mechanism is called typical or classical MDR.
Including surgery, radiation, nuclear therapy etc.
ATP-binding cassette (ABC) transporters:
For developing more effective therapies Identifying the mechanisms leading to intrinsic or acquired multidrug resistance (MDR) is important.
Due to expression of particular proteins results in cancer cells resistance-such as cell-membrane transporters, which can result in an increased efflux of the cytotoxic drugs from the cancer cells, thus lowering their concentrations.
When overexpression of the membrane efflux pumps is involved in MDR .
The resistance mechanism is called typical or classical MDR.
Reasons:
Selection of cells that have :
Increased expression of membrane glycoproteins
Increase in levels of cytoplasmic thiols
Inreasing in deactivating enzymes
Decrease in activating enzymes by changes in specific gene sequences
increase in DNA repair.
Membrane glycoproteins (P-glycoproteins) are responsible for the efflux of drugs from cells and represent a type of Multi Drug Resistance (MDR).
These P-glycoproteins bind and extrude drugs from tumor cells. By increasing pools of cytoplasmic thiols, such as glutathione, the cell increases its ability to destroy reactive electrophilic anticancer drugs.
Reasons:
Selection of cells that have :
Increased expression of membrane glycoproteins
Increase in levels of cytoplasmic thiols
Inreasing in deactivating enzymes
Decrease in activating enzymes by changes in speci

1. Combinating Drug Resistance and Analog Design Presented By: Divya Ashok Dhule M.Pharm (pharmaceutical Chemistry) 1 st year Department of pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur university, Nagpur

2. Content: Drug resistence. Stratergies to Combat antimicrobial resistance. Stratergies to combat anticancer resistance. Genetic principles of drug resistance. Geometric isomers. Fragments of the lead molecule. Variation in interatomic distances.

3. Drug resistance: Microbes are still grow in presence of drug It may lead to treatment failure Spread in a society or community.

4. Mechanisms of Resistance Gene Transfer Transfer of r-genes from one bacterium to another: Conjugation:- make a connecting tube between the 2 bacteria through which plasmid itself can pass. Transduction:-bacteriophage contain plasmid DNA is transferred to another bacterium of same species. Transformation:-Free DNA is picked up from the environment i.e. From a cell belonging to closely related. Transfer of r-genes between plasmids within the bacterium By transposons
By Integrons

5. Transposons:

6. Stratergies to Combat antimicrobial resistance :

7. Stratergies to Combat anticancer resistance: Including surgery, radiation, nuclear therapy etc. ATP-binding cassette (ABC) transporters: For developing more effective therapies Identifying the mechanisms leading to intrinsic or acquired multidrug resistance (MDR) is important. Due to expression of particular proteins results in cancer cells resistance-such as cell-membrane transporters, which can result in an increased efflux of the cytotoxic drugs from the cancer cells, thus lowering their concentrations.
When overexpression of the membrane efflux pumps is involved in MDR . The resistance mechanism is called typical or classical MDR.

8. Genetic principles of resistance: Reasons: Selection of cells that have : Increased expression of membrane glycoproteins Increase in levels of cytoplasmic thiols Inreasing in deactivating enzymes Decrease in activating enzymes by changes in specific gene sequences increase in DNA repair.
Membrane glycoproteins (P-glycoproteins) are responsible for the efflux of drugs from cells and represent a type of Multi Drug Resistance (MDR). These P-glycoproteins bind and extrude drugs from tumor cells. By increasing pools of cytoplasmic thiols, such as glutathione, the cell increases its ability to destroy reactive electrophilic anticancer drugs.

9. More specifically gene encoding the family of glutathione S-transferases. Which catalyze the reaction of glutathione with electrophilic compounds, may be altered so that enzymes are overproduced (gene amplification).
Many drugs bind to DNA require enzymatic activation (prodrugs). The genes encoding these enzymes may be altered so that certain tumor cells no longer produce sufficient quantities of the activating enzymes to allow drugs to be effective.

10. Geometric Isomers: Geometric isomers are molecules in which each of two or more chemical compounds having the same molecular formula but a different geometric arrangement . A n unsaturated compound or ring compound in which rotation around a carbon bond is restricted, as in cis- and trans- configurations. cis- and trans-4-Aminocrotonic acid and were prepared as congeners gamma - aminobutyric acid (GABA) . Cis-4-Aminocrotonic acid Trans-4-Aminocrotonic acid(E is Active)

11. Fragments of lead molecule: Lead molecule Pharmacophore Used in analog design Dissect

12. Stratergy: Bond Disconnection Bonds are broken or removed Polycyclic ring destroyed For example : morphine is lead molecule

13. Eg. Fragments Analog:

14. Variation In Interatomic Distances: Alteration of distances between portions of the pharmacophore of a molecule (or even between other portions of the molecule) may produce profound qualitative and/or quantitative changes in pharmacological actions. Eg. Bis trimethylammonium Polymethylene has autonomic ganglia blocking activity.

15. References: Burger, A. A Guide to the Chemical Basis ofDrug Design, NY, EUA,. Wiley, 1983; p g.No.2 4-29. Gaikwad PL et al., The Use of Bioisosterism in Drug Design and Molecular Modification. American Journal of PharmTech Research 2012,pg.no.320 Patani GA, LaVoie EJ. Bioisosterism: a rational approach in drug design. Chem Rev 1996; pg. No.3147-76.