Arben Kojtari Log

Final Project Topic:
Computer-assisted drug design for the development of novel protease inhibitors using molecular docking algorithms
Link to Final Paper
[Good topic - if you can find a crystal structure in the PDB you can cover both docking and QSAR approaches JCB]

Assignment #1
Compound that will be studied of reported properties will be DCC (N,N-Dicyclohexylcarbodiimide)
Melting Point
34-35 °C ChemicalBook
34-35 °C Oxford MSDS
34.5-37 °C SigmaAldrichsigmaDCC.bmp
36 °C Wolfgram Alpha
33-36 °C Alfa Aesar alfaaesarDCC.bmp
34 °C Wikipedia
35-36 °C Merck Chemicals merckDCC.bmp

Boiling Point
277 °C at 760 mmHg LookChem
122-124 °C at 6 mmHg ChemicalBook
154-156 °C at 11 mmHg Oxford MSDS
154-156 °C at 11mmHg Alfa Aesar alfaaesarDCC.bmp
122 °C at 6mmHg Wikipedia
148-152 °C at 15 hPa Merck Chemicals merckDCC.bmp

1.06 g/cm^3 LookChem
1.247 g/mL (25 °C) ChemicalBook
1.247 g/cm^3 Wolfgram Alpha
1.325 g/cm^3 Wikipedia
0.95 g/cm^3 (40 °C) Merck Chemicals merckDCC.bmp
1.06 g/cm^3 Chem Spider

Flash Point
113.1 °C LookChem
113 °C SigmaAldrich sigmaDCC.bmp
87.78 °C Wolfgram Alpha
138 °C Oxford MSDS
138 °C Alfa Aesar alfaaesarDCC.bmp
113 °C Wikipedia
113 °C Merck Chemicals merckDCC.bmp

LD50 Oral (Rats)
1110 mg/kg Merck Chemicals merckLD50DCC.bmp
400 mg/kg Shanghai Medpep
400 mg/kg LookChemDCClookchemtox.bmp
400 mg/kg ChemCAS
1110 mg/kg Oxford MSDS

Assignment #2
Synthesis and Evaluation of Diphenyl Phosphonate Esters as Inhibitors of the Trypsin-like Granzymes A and K and Mast Cell Tryptase
Jackson, Delwin S. et al.
Journal of Medicinal Chemistry, 1998, 41, 2289-2301
Link to publication
[Full Marks JCB]
  • The cellular immune system is responsible for initiating apoptosis in the body, being initiated primarily by cytotoxic T lymphocytes. Trypsin-like proteases (granzymes) are responsible for cleavage of peptide substrates that are involved in DNA fragmentation (granzyme A, B, and K) as well as other degrading processes (i.e. collagen degradation).
  • Not much research has been performed in studying inhibitors for these proteases, with 3 being reported previously; 4-guanidinobenzoates (inhibits granzyme A only), chloromethyl ketones (irreversible inhibitor of some serine proteases but not granzymes mentioned), and 3-alkoxy-4-chloroisocoumarins (short half-life and has propensity to reactivate granzymes).
  • Peptidyl (alpha-aminoalkyl) phosphonate esters and its derivatives were explored as possible inhibitors for granzymes A, K and trypsin, and were effective in inhibiting chymotrypsin-like proteases. Numerous peptidyl 4-amidinophenylglycine phosphonate diphenyl ester derivatives were synthesized and their inhibitions for these targets were experimentally observed.
  • For human Granzyme A, the best overall inhibitor was Ph-CH2-SO2-Gly-Pro-(4-AmPhGly)P(OPh)2.
  • The glycine at the P3 position of this compound is an effective N-blocking group. The proline residue at the P2 position can fit well into the hydrophobic moiety of the granzyme, specifically granzyme K. k(obv)/[I] = 3650 M-1 s-1 for the best overall inhibitor for granzyme A.
  • Rat Granzyme K showed a higher inhibition with a bulky group at the P3 position of the peptidyl branch. The most effective for this enzyme contained 3,3-diphenylpropanoyl group at the P3 position and a proline residue at the P2 position. k(obv)/[I] = 1830 M-1 s-1. It was suggested that granzyme K is best inhbited with a flexible residue at the P3 position rather than a rigid residue (i.e. glycine for granzyme A and trypsin).
  • Bovine Trypsin's best inhibitor in this study was the same as for Granzyme A, Ph-CH2-SO2-Gly-Pro-(4-AmPhGly)P(OPh)2.. The inhibition values that were observed were k(obv)/[I] = 37060 M-1 s-1
  • Peptidyl phosponate esters have the distinct advantage as being using as effective inhibitors for biological targets since they are stable in water and lack anti-coagulant effects (which is an apparent side effect of these class of compounds).

Assignment #3
FAQ Question:

17. List and briefly describe 5 sources that allow structure searches for organic compounds?

1. Scifinder
Start by clicking on explore substances tab on upper portion of website after login. Scifinder allows exact or substructure searches, the ability to sort out different conditions (i.e. solvent), literature that provides in detail reaction conditions, provides yields from previous research, check commercial availability, and the type of studies that the user wishes to focus on, such as analytical or biological studies. Scifinder contains numerous refinement tools to aid the user to specify as needed. Site requires a subscription for use.

2. Beilstein Crossfire
Beilstein is similar to Scifinder that it provides very detailed descriptions of the organic compound that is drawn. Both exact and substructure searches are allowed. Can also refine searches based on the molecular weight of the compound as well as other properties.
Site requires a subscription for use.

3. Organic Syntheses
Site requires ChemDraw plugin. The Organic Syntheses website will also allow a search through the journal volume, author name, substructure, reactions involving the organic compound drawn, etc. Does not require a subscription.

4. Chem Spider
Chem Spider is a useful resource to not only draw the organic compound, but provides a skeleton search as an option. Users can refine search by properties (including rule of 5, MW, refractive index, boiling point, melting point, density, flash point, etc) as well as the data source and type. Does not require a subscription.

5. Sigma Aldrich
Commercial chemical provider that allows the user to check the commercial availability of the compound by Sigma Aldrich. Site allows an exact or substructure search, as well as additional criteria (i.e. boiling point, melting point, molecular weight) to refine searches. Also useful for quickly identifying basic properties of compounds that are commercially available through the search tool. Does not require a subscription.

-Arben Kojtari