1. The progression is HTS hits to Lead Series to Candidate Drugs to Market Drug.

This progression is used to show the process of implementing drugs into the mar
ket and also shows the likelihood being highly improbable. The process begins by
looking at lots of drugs, then identifying a proper group that could function a
s the Lead Drug. After this, Candidate Drugs with potential (based on desired pr
operties) are chosen. After many tests and implementation runs, only a few of th
ese Candidate Drugs get published as Market Drugs. To be a Market Drug, the drug
must be proven to have no detrimental effects. In reality, the probability of a
drug reaching Market Drug status is one in a million from when it was initially
tested via HTS.
2. The authors were looking to see if scientists were observing correct properti
es in searching for good marketplace drugs. Since the progression is long and ty
pically improbable itself, it is important to base new drug discoveries on a goo
d set of properties from initial HTS hits. The research done in this paper looks
to see if there are any trends between good drugs and properties that initially
pass HTS tests to see if they are looking at the correct properties that lead t
o Market Drugs.
3. logP is also known as the partition coefficient. It is defined as the ratio o
f concentrations in a compound to a mixture of two immiscible phases (1-octanol
and water). In terms of Lipinski's Rules, a logP < 5 is generally good to be tak
en as an oral drug.
4. Phases I, II, and III refer to clinical trial phases of candidate drugs befor
e they become published as market drugs. Typically, one in every ten candidate d
rugs gets published as a market drug after they pass through Phases I, II, and I
II. In Phase I, the drug is given to a small group of people to test it (PK/PD c
haracteristics). In Phase II, the drug is given to a larger group of people to c
ontinue monitoring side effects and conditions (biological effects). Lastly, in
Phase III, the drug is given to a very large group of people before it can be re
leased as a market drug (effectiveness).
5. Drugs that are effective at concentrations over 1 nM have MW > 425, LogP > 4.
25, and LogSw < -4.75.
6. new chemical entity
7. Molecular Weight < 500
LogP < 5.0
Number of Hydrogen Bond Donors (HBD) < 5
Number of Hydrogen Bond Acceptors (HBA) < 10
8. The analysis that the authors conduct is more restrictiveregarding the weight (
100 as opposed to 500), logP (4 as opposed to 5), and the lead drugs need one ri
ng and two flexible bonds.
9. The equation to determine LogSw is LogSw (mol/L) = 0.796 - 0.854*LogP - 0.007
28*MW + Corrections. Therefore, the predictors for LogSw are LogP and Molecular
Weight. Corrections are based on 15 structure types depending on the available m
elting points (e.g. alcohols, acids, selected phenols, nitros, amines, alkyl pyr
idines, amino acids, multi-nitrogen types, etc.).
10. Figure 1 shows a series of chemical structures and the derivation of market
drugs from initial lead drugs. More specifically, it shows the derivation of ome
prazole, clozapine, butaclamol, and methylphenidate.
11. 750
12. poor solubility and poor permeability