The document discusses why drugs tend to have certain molecular structures and properties. It explains that drugs must be small molecules to bind to protein targets, specifically those with deep hydrophobic pockets. Small molecules can maximize interactions through heterocyclic rings that provide a high density of functional groups oriented in space. Heterocycles allow drugs to complement the interior surfaces of pockets through hydrophobic, aromatic, and hydrogen bonding interactions. This allows for high binding affinity needed for drug action.
Drugs must penetrate cellular membranes and bind to intracellular protein targets to be effective. They are generally small molecules that are somewhat hydrophobic to be bioavailable. Small molecules can only bind to proteins with deep hydrophobic pockets. To complement these pockets and maximize interactions, drugs need to present functional groups in an oriented manner. Heterocycles and aromatic systems allow for this by providing multiple functional groups on a flat surface. Heterocycles also enable facile derivatization to improve drug properties.
Stable isotope labeled organic molecules have various applications in the pharmaceutical industry. Deuterium was discovered in 1932 and is used to study reaction mechanisms through kinetic isotope effects. Replacing hydrogen with deuterium in drug molecules can alter their metabolism and pharmacokinetics, potentially improving properties. Stable isotopes are also used as reference standards in mass spectrometry to improve quantification of drugs and metabolites. The global market for stable isotope labeled compounds was estimated at $220 million in 2013, with the pharmaceutical industry as the largest segment due to increasing clinical trials and quantification techniques. Challenges include high costs, but availability of resources in countries like India may allow for lower costs.
This document lists 41 publications by Wolfgang Brill related to solid phase organic synthesis and oligonucleotide chemistry. The publications span from 1989 to 2014 and include journal articles, book chapters, and patent applications. The publications cover topics such as solid phase synthesis of heterocycles, purines, and oligonucleotides; C-C and C-X bond forming reactions on solid support; and the development of protecting groups for use in solid phase synthesis.
Knowledge-based chemical fragment analysis in protein binding sitesCresset
This document discusses an approach to selecting likely binding molecules for a protein target based on analyzing known protein-ligand interactions from the Protein Data Bank (PDB). It describes extracting "fragments" from ligands that form hydrogen bonds to common amino acids like Aspartic acid, Glutamic acid, Arginine, and Histidine. These fragments are analyzed to determine common structural motifs that preferentially interact with certain amino acid side chains. This knowledge could help medicinal chemists design new compounds likely to bind a given protein binding site.
This document lists invited presentations, publications, and patent applications by Rikki Alexander related to pharmaceutical research. It includes presentations on phosphodiesterase inhibitors for asthma treatment from 2002-2003. It also lists several patent applications and publications from 2008-2015 on small molecule inhibitors for conditions like TNF activity and PI3 kinase. The publications involve collaborations and are focused on developing drug candidates and understanding disease mechanisms.
Daryl Walter has authored or co-authored 34 publications and patents related to P2X7 receptor modulators and BACE-1 inhibitors. The publications describe the synthesis and testing of various chemical derivatives to modulate the P2X7 receptor, including imidazoles, pyrazoles, piperazines, and morpholines. Additional work involved optimizing hydroxyethylamine inhibitors of the BACE-1 enzyme for treatment of Alzheimer's disease.
1) The document discusses the historical development of radiographic contrast media from its earliest uses in the late 19th century to the development of tri-iodinated benzene derivatives and modern low-osmolar non-ionic contrast agents.
2) It covers the ideal characteristics, classification, and basic chemistry of iodinated contrast media including differences between ionic and non-ionic monomers and dimers.
3) The risks of contrast media administration are discussed including predictable chemo-toxic reactions affecting tissues and organ systems as well as unpredictable anaphylactoid reactions.
Drugs must penetrate cellular membranes and bind to intracellular protein targets to be effective. They are generally small molecules that are somewhat hydrophobic to be bioavailable. Small molecules can only bind to proteins with deep hydrophobic pockets. To complement these pockets and maximize interactions, drugs need to present functional groups in an oriented manner. Heterocycles and aromatic systems allow for this by providing multiple functional groups on a flat surface. Heterocycles also enable facile derivatization to improve drug properties.
Stable isotope labeled organic molecules have various applications in the pharmaceutical industry. Deuterium was discovered in 1932 and is used to study reaction mechanisms through kinetic isotope effects. Replacing hydrogen with deuterium in drug molecules can alter their metabolism and pharmacokinetics, potentially improving properties. Stable isotopes are also used as reference standards in mass spectrometry to improve quantification of drugs and metabolites. The global market for stable isotope labeled compounds was estimated at $220 million in 2013, with the pharmaceutical industry as the largest segment due to increasing clinical trials and quantification techniques. Challenges include high costs, but availability of resources in countries like India may allow for lower costs.
This document lists 41 publications by Wolfgang Brill related to solid phase organic synthesis and oligonucleotide chemistry. The publications span from 1989 to 2014 and include journal articles, book chapters, and patent applications. The publications cover topics such as solid phase synthesis of heterocycles, purines, and oligonucleotides; C-C and C-X bond forming reactions on solid support; and the development of protecting groups for use in solid phase synthesis.
Knowledge-based chemical fragment analysis in protein binding sitesCresset
This document discusses an approach to selecting likely binding molecules for a protein target based on analyzing known protein-ligand interactions from the Protein Data Bank (PDB). It describes extracting "fragments" from ligands that form hydrogen bonds to common amino acids like Aspartic acid, Glutamic acid, Arginine, and Histidine. These fragments are analyzed to determine common structural motifs that preferentially interact with certain amino acid side chains. This knowledge could help medicinal chemists design new compounds likely to bind a given protein binding site.
This document lists invited presentations, publications, and patent applications by Rikki Alexander related to pharmaceutical research. It includes presentations on phosphodiesterase inhibitors for asthma treatment from 2002-2003. It also lists several patent applications and publications from 2008-2015 on small molecule inhibitors for conditions like TNF activity and PI3 kinase. The publications involve collaborations and are focused on developing drug candidates and understanding disease mechanisms.
Daryl Walter has authored or co-authored 34 publications and patents related to P2X7 receptor modulators and BACE-1 inhibitors. The publications describe the synthesis and testing of various chemical derivatives to modulate the P2X7 receptor, including imidazoles, pyrazoles, piperazines, and morpholines. Additional work involved optimizing hydroxyethylamine inhibitors of the BACE-1 enzyme for treatment of Alzheimer's disease.
1) The document discusses the historical development of radiographic contrast media from its earliest uses in the late 19th century to the development of tri-iodinated benzene derivatives and modern low-osmolar non-ionic contrast agents.
2) It covers the ideal characteristics, classification, and basic chemistry of iodinated contrast media including differences between ionic and non-ionic monomers and dimers.
3) The risks of contrast media administration are discussed including predictable chemo-toxic reactions affecting tissues and organ systems as well as unpredictable anaphylactoid reactions.
1. The document discusses the history and evolution of drug discovery approaches, contrasting early genomic and target-based methods with more recent phenotypic screening.
2. It notes that phenotypic screening has proven more successful in discovering first-in-class drugs compared to target-based approaches.
3. The document examines networks of drug structures and biological targets, finding they differ significantly, suggesting conservation of certain chemical motifs regardless of target similarity.
Where is drug discovery going? Christopher A. Lipinski outlines several key points about changes in drug discovery approaches. He notes that the traditional target-based approach has limitations and that phenotypic screening, drug repurposing, and multi-targeted discovery may be more promising avenues. Lipinski also discusses challenges with academic target identification and the need for greater industry-academic collaboration to bridge the "translational valley of death".
Application of deuterium in drug discoveryRahul B S
Deuterium, a stable isotope of hydrogen, can be used in drug discovery to modify drugs' pharmacokinetic and pharmacodynamic properties. Replacing hydrogen with deuterium (deuteration) utilizes the kinetic isotope effect to slow metabolism and increase drug exposure. Several deuterated drugs have been clinically tested, including D1-halothane, fludalanine, D6-nifedipine, and deuterated nevirapine, which all showed improved properties over their non-deuterated counterparts. The deuterium chemical entity platform allows for more efficient drug development by building upon existing drugs and clinical compounds. Challenges include deuterium exchange and metabolic switching, but overall deuter
Linezolid is a small molecule antibiotic developed by DuPont and Pharmacia that binds to the 50S ribosomal subunit to inhibit bacterial protein synthesis. It was synthesized in 1993 and approved by the FDA in 2000. Linezolid is orally bioavailable and effective against gram-positive bacteria including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. It represents an important treatment option for difficult to treat gram-positive infections.
1. The document discusses using databases like the Protein Data Bank (PDB) to better understand protein receptors and target recognition through data mining and analyzing protein structures and interactions.
2. It describes research tools for discovering and characterizing protein receptors, and how they can be used to undertake high-throughput hypothesis generation for protein-drug interactions on a proteome-wide scale.
3. The analysis of the Mycobacterium tuberculosis proteome and identification of potential drug targets from existing drugs is provided as an example of this approach.
The drug discovery process involves several steps:
1) Hits from high-throughput screening are identified, which may have many potential scaffolds.
2) Hit-to-lead involves synthesizing many compounds to determine structure-activity relationships and improve properties.
3) Lead optimization aims to increase potency, selectivity, and in vivo efficacy while maintaining favorable properties. Efficient synthesis and parallel chemistry methods are important throughout the process.
Microbial Biosyntheses of Contraceptive HormonesNicholas Gober
This is the written component of a two-fold project (oral presentation & written report) that I co-authored along with two of my Yellow Jacket peers. The project was an assignment for an advanced upper-level chemistry course called Drug Design, Development, & Delivery (CHEM 4765).
Godlee clinical trial data for all drugs in current useMarilyn Mann
1) The editorial argues that clinical trial data for all drugs currently in use should be made publicly available for independent scrutiny, as drug companies have systematically misreported and withheld data from clinical trials, endangering patients.
2) It highlights GSK's recent commitment to allow access to anonymized patient-level data from clinical trials as a positive step, but notes that independent researchers should be able to access all clinical trial data once regulatory approval is granted.
3) The editorial expresses frustration that Roche has withheld about 60% of clinical trial data on Tamiflu from the Cochrane review and regulators, costing taxpayers billions, and calls on Roche to release the full data to allow independent evaluation of Tamif
This document summarizes metal-organic frameworks (MOFs), including their properties and applications. MOFs are highly porous materials formed by combining metal ions or metal clusters with organic ligands. They have extremely large surface areas, often exceeding 7,000 m2/g. Due to their tunable porous structures, MOFs show promise for applications such as gas storage, carbon capture, catalysis, and luminescence. While MOF research has advanced significantly in recent decades, further developing their potential applications and improving stability remains an active area of research.
This document summarizes reactive oxygen species (ROS) and their role in periodontal disease. It begins by defining antioxidants, free radicals, and oxidative stress. It describes the various ROS like superoxide, hydroxyl radical, nitric oxide, and peroxynitrite. It outlines the sources of free radicals including internal sources like mitochondria and external sources like smoking. It details the effects of ROS on lipids, proteins, DNA and tissues. This causes cellular injury and death. Evidence shows elevated ROS in periodontal disease tissues and its role in tissue damage by affecting gingival cells, bone, ground substance, and collagen. The document also discusses antioxidant defense systems in the body like vitamins C and E, carotenoids,
This document discusses the presence of pharmaceuticals in water sources and their potential negative impacts. It summarizes that pharmaceuticals commonly found include antibiotics, steroids, and cancer drugs. These substances can inhibit growth, reduce reproduction, and disrupt endocrine systems in aquatic life. The FDA regulatory process is criticized for allowing many drugs onto the market without consideration of environmental impacts. The Great Lakes Environmental Law Center petitioned the FDA to strengthen its review process given evidence that very low levels of these substances still harm the environment.
This document provides an overview of biomolecules and the human genome project. It discusses the major causes of disease, including physical, chemical, biological, genetic, and nutritional factors. The human genome project mapped over 90% of the human genome, identifying approximately 75,000 genes. Proteomics studies protein interactions, though only 1% of protein structures have been determined. Predictions for the future of medicine over the next 40 years include widespread genetic testing and screening, gene therapies for many conditions, and personalized medicine based on genomic data.
Why do drugs look the way they do_Conference Paper.PDFWolfgang Brill
This document discusses why drugs often have heterocyclic structures and look the way they do. It explains that heterocycles provide the highest density of functional groups in a small space, allowing drugs to optimally interact with biological targets. Drugs must be small enough to bind targets while also having properties that allow oral absorption. The document then discusses how drugs bind to targets through a combination of interactions like hydrogen bonding, hydrophobic interactions, and van der Waals forces. It argues that for small drugs to tightly bind targets, the target must have predominantly hydrophobic pockets that complement the shape of the drug.
The document discusses protein-drug binding, including the two main classes of binding: intracellular and extracellular. It describes the reversible mechanisms of binding such as hydrogen bonds and hydrophobic bonds. Key factors that affect protein-drug binding are the physicochemical properties of the drug and protein, their concentrations, and the number of binding sites. The significance of protein binding is that the bound fraction of a drug is pharmacologically inactive.
This document provides an overview of biochemistry, including its definition, objectives, and relationships to other life sciences. It discusses that proteins are the most abundant biomolecules in cells, consisting of linear polymers of 20 amino acids. The major techniques used in biochemistry to study cellular components and reactions are also summarized.
This document discusses guidelines for drug-like molecular properties based on analyses of properties of known drugs. It describes the "rule of 5" proposed by Lipinski based on over 2,000 drugs, which found that 90% of orally bioavailable drugs have molecular weight less than 500 Daltons, logP less than 5, fewer than 5 hydrogen bond donors, and fewer than 10 hydrogen bond acceptors. It also discusses refinements to the rule of 5 proposed by other researchers, including the "rule of 4" for early stage leads and the "rule of 3" for fragments used in fragment-based drug discovery. The document emphasizes that following these guidelines promotes a higher probability of developing compounds that are orally bioavailable and pharmac
1. The document discusses the history and evolution of drug discovery approaches, contrasting early genomic and target-based methods with more recent phenotypic screening.
2. It notes that phenotypic screening has proven more successful in discovering first-in-class drugs compared to target-based approaches.
3. The document examines networks of drug structures and biological targets, finding they differ significantly, suggesting conservation of certain chemical motifs regardless of target similarity.
Where is drug discovery going? Christopher A. Lipinski outlines several key points about changes in drug discovery approaches. He notes that the traditional target-based approach has limitations and that phenotypic screening, drug repurposing, and multi-targeted discovery may be more promising avenues. Lipinski also discusses challenges with academic target identification and the need for greater industry-academic collaboration to bridge the "translational valley of death".
Application of deuterium in drug discoveryRahul B S
Deuterium, a stable isotope of hydrogen, can be used in drug discovery to modify drugs' pharmacokinetic and pharmacodynamic properties. Replacing hydrogen with deuterium (deuteration) utilizes the kinetic isotope effect to slow metabolism and increase drug exposure. Several deuterated drugs have been clinically tested, including D1-halothane, fludalanine, D6-nifedipine, and deuterated nevirapine, which all showed improved properties over their non-deuterated counterparts. The deuterium chemical entity platform allows for more efficient drug development by building upon existing drugs and clinical compounds. Challenges include deuterium exchange and metabolic switching, but overall deuter
Linezolid is a small molecule antibiotic developed by DuPont and Pharmacia that binds to the 50S ribosomal subunit to inhibit bacterial protein synthesis. It was synthesized in 1993 and approved by the FDA in 2000. Linezolid is orally bioavailable and effective against gram-positive bacteria including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. It represents an important treatment option for difficult to treat gram-positive infections.
1. The document discusses using databases like the Protein Data Bank (PDB) to better understand protein receptors and target recognition through data mining and analyzing protein structures and interactions.
2. It describes research tools for discovering and characterizing protein receptors, and how they can be used to undertake high-throughput hypothesis generation for protein-drug interactions on a proteome-wide scale.
3. The analysis of the Mycobacterium tuberculosis proteome and identification of potential drug targets from existing drugs is provided as an example of this approach.
The drug discovery process involves several steps:
1) Hits from high-throughput screening are identified, which may have many potential scaffolds.
2) Hit-to-lead involves synthesizing many compounds to determine structure-activity relationships and improve properties.
3) Lead optimization aims to increase potency, selectivity, and in vivo efficacy while maintaining favorable properties. Efficient synthesis and parallel chemistry methods are important throughout the process.
Microbial Biosyntheses of Contraceptive HormonesNicholas Gober
This is the written component of a two-fold project (oral presentation & written report) that I co-authored along with two of my Yellow Jacket peers. The project was an assignment for an advanced upper-level chemistry course called Drug Design, Development, & Delivery (CHEM 4765).
Godlee clinical trial data for all drugs in current useMarilyn Mann
1) The editorial argues that clinical trial data for all drugs currently in use should be made publicly available for independent scrutiny, as drug companies have systematically misreported and withheld data from clinical trials, endangering patients.
2) It highlights GSK's recent commitment to allow access to anonymized patient-level data from clinical trials as a positive step, but notes that independent researchers should be able to access all clinical trial data once regulatory approval is granted.
3) The editorial expresses frustration that Roche has withheld about 60% of clinical trial data on Tamiflu from the Cochrane review and regulators, costing taxpayers billions, and calls on Roche to release the full data to allow independent evaluation of Tamif
This document summarizes metal-organic frameworks (MOFs), including their properties and applications. MOFs are highly porous materials formed by combining metal ions or metal clusters with organic ligands. They have extremely large surface areas, often exceeding 7,000 m2/g. Due to their tunable porous structures, MOFs show promise for applications such as gas storage, carbon capture, catalysis, and luminescence. While MOF research has advanced significantly in recent decades, further developing their potential applications and improving stability remains an active area of research.
This document summarizes reactive oxygen species (ROS) and their role in periodontal disease. It begins by defining antioxidants, free radicals, and oxidative stress. It describes the various ROS like superoxide, hydroxyl radical, nitric oxide, and peroxynitrite. It outlines the sources of free radicals including internal sources like mitochondria and external sources like smoking. It details the effects of ROS on lipids, proteins, DNA and tissues. This causes cellular injury and death. Evidence shows elevated ROS in periodontal disease tissues and its role in tissue damage by affecting gingival cells, bone, ground substance, and collagen. The document also discusses antioxidant defense systems in the body like vitamins C and E, carotenoids,
This document discusses the presence of pharmaceuticals in water sources and their potential negative impacts. It summarizes that pharmaceuticals commonly found include antibiotics, steroids, and cancer drugs. These substances can inhibit growth, reduce reproduction, and disrupt endocrine systems in aquatic life. The FDA regulatory process is criticized for allowing many drugs onto the market without consideration of environmental impacts. The Great Lakes Environmental Law Center petitioned the FDA to strengthen its review process given evidence that very low levels of these substances still harm the environment.
This document provides an overview of biomolecules and the human genome project. It discusses the major causes of disease, including physical, chemical, biological, genetic, and nutritional factors. The human genome project mapped over 90% of the human genome, identifying approximately 75,000 genes. Proteomics studies protein interactions, though only 1% of protein structures have been determined. Predictions for the future of medicine over the next 40 years include widespread genetic testing and screening, gene therapies for many conditions, and personalized medicine based on genomic data.
Why do drugs look the way they do_Conference Paper.PDFWolfgang Brill
This document discusses why drugs often have heterocyclic structures and look the way they do. It explains that heterocycles provide the highest density of functional groups in a small space, allowing drugs to optimally interact with biological targets. Drugs must be small enough to bind targets while also having properties that allow oral absorption. The document then discusses how drugs bind to targets through a combination of interactions like hydrogen bonding, hydrophobic interactions, and van der Waals forces. It argues that for small drugs to tightly bind targets, the target must have predominantly hydrophobic pockets that complement the shape of the drug.
The document discusses protein-drug binding, including the two main classes of binding: intracellular and extracellular. It describes the reversible mechanisms of binding such as hydrogen bonds and hydrophobic bonds. Key factors that affect protein-drug binding are the physicochemical properties of the drug and protein, their concentrations, and the number of binding sites. The significance of protein binding is that the bound fraction of a drug is pharmacologically inactive.
This document provides an overview of biochemistry, including its definition, objectives, and relationships to other life sciences. It discusses that proteins are the most abundant biomolecules in cells, consisting of linear polymers of 20 amino acids. The major techniques used in biochemistry to study cellular components and reactions are also summarized.
This document discusses guidelines for drug-like molecular properties based on analyses of properties of known drugs. It describes the "rule of 5" proposed by Lipinski based on over 2,000 drugs, which found that 90% of orally bioavailable drugs have molecular weight less than 500 Daltons, logP less than 5, fewer than 5 hydrogen bond donors, and fewer than 10 hydrogen bond acceptors. It also discusses refinements to the rule of 5 proposed by other researchers, including the "rule of 4" for early stage leads and the "rule of 3" for fragments used in fragment-based drug discovery. The document emphasizes that following these guidelines promotes a higher probability of developing compounds that are orally bioavailable and pharmac
4. Brill, May 2002 The Blockbusters 2000: Mostly Small Molecules Prilosec Prevacid Lipidor Zocor Prozac Celebrex Zoloft Zyprexa Epogen, Procrit:
5. Brill, May 2002 Cyclic molecules provide the highest density of atoms per surface, heterocycles the highest density of chemical functionalities with well-defined orientation in space per surface. X R R Various functional groups H Hydrophobic residues C - electron clouds H Polar residues
6. Why Do Drugs Look the Way they Do? Lets look at the Targets! Brill, May 2002
7.
8. Brill, May 2002 L. S. Goodman et al. , Eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics (McGraw-Hill, New York, ed. 9, 1996).
11. Why Do Drugs Look the Way they Do? How do Drugs get to their Targets! Brill, May 2002
12. Brill, May 2002 Drugs can be administerd in many ways They have to penetrate organ barriers and cell membranes to reach their target
13. Brill, May 2002 Since many targets are intracellular, cellular membranes present a severe obstacle 1 outside the cell 2 inside the cell 3 freeze fracture passes through the middle bilayer protein 4,5,7,8, 9 integral membrane proteins 6,11 peripheral membrane proteins 10 carbohydrate residues Singer, S. J.; Nicolson, G. L. Science (Washington, D. C.) 175 ( 1972 ) 723
14. Brill, May 2002 Lüllmann, H.; Mohr, K.; Ziegler, A. Taschenatlas der P harmakologie, 3rd ed. Georg Thieme Verlag Stuttgart, New York 1996 Transport of drugs Passive diffusion rule of 5 obligatory Active transport drugs use systems for: amino acids L-DOPA basic polypeptides amino glycosides Receptor mediated transport 1,2: binding to receptor 3: adaptin addition 4: accumulation of receptors 5: formation of vesicle 6-8: formation of endosome and recycling of receptor 9: intracellular distribution via endosome vesicular transport out out in
15.
16. Distribution of “rule-of-5 properties” among drugs in phase II development Brill, May 2002 Lipinski C. A. et al. Adv. Drug Delivery Rev. 23 ( 1997 ) 3-25
17. Brill, May 2002 Calculation of the polar surface area and correlation with bioavailability Bioavailability type: r 2 (TPSA) Oral drug absorption: 0.91 Caco-2-permeabilty: 0.56-0.96 Blood brain barrier: 0.66-0.84 Human jejunum permeability: 0.75 Ertl et al. J. Med. Chem. 43 ( 2000 ) 3714-3717
18. Brill, May 2002 Drugs Bioavailability imposes stringent restrictions upon the chemical and physical properties of drugs How can the drug-like compounds interact with proteins? All compounds Rule - of - 5 compounds
20. Brill, May 2002 H-bonds ? HOH ........ OH 2 - 6.4 Kcal mol -1 H 2 O ........ HSCH 3 - 3.2 Kcal mol -1 HOH ........ S(H)CH 3 - 3.1 Kcal mol -1 Imidazolinium/water - 14.0 Kcal mol -1 CH 3 CO 2 - ....... HOH - 19.0 Kcal mol -1 S int H DW S rt S vib H DR RW S W + +
21.
22. Brill, May 2002 Hydrophobic interactions? drug poorly solvated by water alignment with target surface water does not bind well to target site: can readily be displaced
23. Brill, May 2002 Mostly Hydrophobic Interactions: ATP complements its binding site in CDK2 Eksterowicz, John E. et al. J. Mol. Graphics & Modelling 20 ( 2002 ) 469-477.
24. Example for hydrophobic interactions in nature: Brill, May 2002 Multiple -stacking of aromatics in a telomerase complex Horvath, M. P. et al. Cell 95 ( 1998 ) 963-974
25. Brill, May 2002 Mostly hydrophobic interactions: Staurosporine binds CDK2 Noble, M. E. M. et al. Pharmacol. Ther. 82 ( 1999 ) 269-278
26. Brill, May 2002 Contributions of functional groups to binding Andrews, P. R. et al. J. Med. Chem. 27 ( 1984 ) 1648-1657 DOF -0.7 -0.7- -1.0 C(sp 2 ) 0.7 0.6- 0.8 C(sp 3 ) 0.8 0.1- 1.0 N + 11.5 11.4- 15.0 N 1.2 0.8- 1.8 CO 2 - 8.2 7.3- 10.3 OPO 3 - 10.0 7.7- 10.6 OH 2.5 2.5- 4.0 C=O 3.4 3.2- 4.0 O,S 1.1 0.7- 2.0 halogen 1.3 0.2- 2.0 Group Energy range over (Kcalmol -1 ) 200 cpds. DOF: degrees of freedom
27. Brill, May 2002 X R R Fixation of functional groups in space H Alignment with target surface C - Interactions H H-bond The greater the surface of a drug involved in interactions with its target, the greater the binding!
28. Brill, May 2002 The interactions of a kinase inhibitor with the interior of a binding pocket Gray, N . S. et al. Science (Washington, D. C.) 281 ( 1998 ) 533-538
29.
30.
31. Brill, May 2002 All proteins Proteins with deep hydrophobic pockets Proteins binding to rule - of - 5 compounds All compounds Rule - of 5 compounds Targets Drugs
32. Drug Target Selection Only proteins with deep hydrophobic pockets are suitable for low MWt. Ligands... Brill, May 2002 ...such as proteins binding nucleotide cofactors
33.
34. Brill, May 2002 Blume-Jensen, P . et al. Nature (London, U. K.) ( 2001 ) 411, 355-365 Various receptors with kinase-domains intracellular extracellular kinase domain