The perspective of molecular docking:A killer application to drug design is emerging

jianquan jianquan at eden.rutgers.edu
Sun Feb 17 13:20:27 EST 2002

The perspective of molecular docking: 
A killer application to drug design is emerging

by Jianquan Chen 
Email: chen_jianquan at yahoo.com

As structural genomics initiative begins to bring more and more 3D  
macromolecular structures, the work involved to validate all these 
potential targets, to demonstrate their therapeutic relevance, and to 
leads will become heavily dependent on the high-throughput screening 
technologies such as automated molecular docking.

Now it makes more and more chemical compounds screened because a new 
has to meet more and stricter requirements. Thus high-throughput
screening (HTS) technology has played an increasingly important role in 
drug development. And for many pharmaceutical companies, HTS is now an 
essential component to identify leads.

Molecular docking over a large scale virtual compound database is a 
kind of
virtual HTS technology. Molecular docking is used to predict the bound 
conformation of the ligand to the receptor. It connects the structural 
bioinformatics and drug design. Straightforwardly speaking, it is a 
to mine gold from the structural bioinformatics data. It can be divided 
3 classes, rigid ligand/rigid receptor, flexible ligand/rigid receptor, 
flexible ligand/(partially) flexible receptor docking. Rigid 
receptor docking is very fast but not detailed. flexible ligand/ 
flexible receptor docking is too complicated to be used to screen a 
scale database. So we only discuss flexible ligand/rigid receptor 

A docking problem can be divided into search algorithm and scoring 
search algorithm should be efficient enough to find the lowest energy 
configuration or conformation. The scoring function should be able to 
distinguish a correct binding mode from other putative modes. I only 
discuss search algorithm here because the progress on the search 
and the computer will remove the hardware obstacle for the flexible 
rigid receptor docking to enter the medicinal chemistry lab soon.

AEDock1.1, a new release of AEDock, where a new technology is 
can dock XK263, a bulky ligand with 10 rotatable bonds, into HIV-1 
in 23.4 seconds using a tolerance of 0.01nm rmsd with a success rate of 
on a PC with an AMD 750M CPU+256M SDRAM. Please read the results of 
AEDock1.1 at 
http://www20.brinkster.com/jianquan/aedock11/default.asp .It is a WHOLE 
MOLECULE-BASED docking program and so avoids the disadvantages of the 
fragment-based docking approaches. Based on the rotatable bond 
table from Bohdan W., it is estimated that 2 PC with 2.2GHz Intel CPU 
screen 1M drug-like compounds with 0-10 rotatable bonds in 1 week. 
follow the above link to see how it is estimated.

Comparison of molecular docking and real HTS 
1.Molecular docking over a compound database is more productive and 
cost-efficient than a real HTS. 
I list the disadvantages of real HTS here:
1. HTS is no guarantee of success.
2. Establishing a robust assay for a new target takes time and money. 
Hit rates against some receptors are reported to be very low, 
screening of very large numbers of com-pounds (tens to hundreds of 
Collections of synthesized compounds or natural products often contain 
less chemical diversity than is desired, are not bottomless resources, 
are very time-consuming to replenish.
3. Techniques such as combinatorial chemistry offer the potential for 
synthesizing very large libraries of compounds, but in practice this 
is time-consuming for drug-like com-pounds and may still produce 
of relatively restricted diversity.
4. What is the most important is that a real HTS system and a real 
compound database are so expensive that only companies can afford them.
A normal medicinal chemistry lab can't afford it.

Bohdan W. etc. used a 64-processor SGI Origin2000 to dock a 1.1 million 
drug-like compounds and it took the workstation 6 days to finish the 
These compounds were docked into human alpha-estrogen receptor. after 
being docked and filtered by some supplementary descriptors, a set 
37 commercially available compounds were chosen to be assayed in a 
competitive radio-ligand binding assay. 21 exhibited an inhibition 
( Ki ) of 300 nM (nanomolar) or less, with the best compounds at 8 nM. 
the structural novelty of the hits (compounds known to possess 
activity or to be structurally similar to known ligands were excluded 
assay), this represents a very positive result, demonstrating that 
screening can readily identify potent ligands from a variety of 

Maybe you will say:"a 64-processor SGI Origin2000 is very expensive." 
if AEDock1.1 is used, then we only need to buy 2 PC 2.2GHz Intel CPU. A 
Dell Dimension 8200 PC with 2.2G Pentium 4 CPU and 256MB PC800 RDRAM 
(Rambus dynamic RAM) only costs you $1,689 in Feb 13,2002. The total 
is about $3,300. Several months later they can be bought at a cheaper 
price. I predict in the end of 2002 a PC with one single CPU can screen 
1M drug-like compounds with 0-10 rotatable bonds using whole molecule-
flexible ligand/rigid receptor docking approach in 1 week because 
performances of CPU and search algorithm are keeping increasing. It 
that the hardware obstacle for the flexible docking/rigid receptor 
to enter normal medicinal chemistry lab will disappear soon.

Comparison of molecular docking and pharmacophore queries or focused 2-
the flexible ligand/rigid docking is more detailed and more objective 
than pharmacophore queries or focused 2-D property. Application of 
pharmacophore queries or focused 2-D property profiles may significantly
inhibit the diversity of the compound subset because they are biased 
by the properties of known ligands. In contrast, the molecular docking
program can process an entire chemical database with minimal 
pre-filtering (e.g., to eliminate unstable or toxic moieties) so that 
the final selection is based on the quality of the docked models rather 
than a subjective opinion of what properties are expected in a ligand. 
This route is a very promising one to find structurally novel ligands, 
which may make receptor interactions similar to known ligands.
The roles molecular docking plays in the drug design
1. find leads.
2. provide groups for chemists to modify the leads. When compounds are 
docked into the receptor,  the groups interacting with the subsites of 
the receptor should be ranked. Maybe the groups with good ranking plus 
leading compounds will lead to final products. (up to now I didn't find 
any paper on this role of the molecular docking, please tell me if you 
find any paper on this. )

So molecular docking provides not only leading compounds, but also 
you how to modify the leads. Oops, molecular docking provides a whole 
solution for drug discovery.

It sounds molecular docking very promising and will be popular soon.
Then why not to invest your money or energy in it? Please contact me 
if you are interested. Email:chen_jianquan at yahoo.com, Phone:(USA)732-

In a word, the molecular docking will become a killer application to 
design. It will enter the normal medicinal chemistry labs, not only the 
big pharmaceutical companies.

The obstacles for the molecular docking to enter the medicinal 
chemistry lab
1. The virtual compound database. Now most of the scientist uses ACD-3D 
or ACD-SC from MDL as the compound database for screening. It will cost 
you about $15,000 to get a license of ACD-3D and ACD-SC on a single 
"Datastation" per year. But MDL allows you to share the ISIS databases 
with other scientists and so it will lower your cost. In addition you 
need a license of Enterprise Oracle database. It seems the database 
you lots of money. There is an alternative solution. A free NCI 3D 
database can be stored in free database such as Mysql. After being 
the final set of compound can be submitted to www.chemexper.com to know 
the compound is commercially available. In addition Oracle database is 
difficult for a chemist or molecular modeler to maintain. 

2. The available 3D macromolecular structures. Most of the 3D 
of macromolecules are not available.  Fortunately, structural genomics 
initiative begins to bring more and more 3D macromolecular structures 
maybe computational protein folding will bring some reliable structures.

3. The scoring functions and the accuracy of the 3D macromolecular 
Not all crystallographic structures can be reproduced because the 
function can't distinguish a correct binding mode from other putative 
for some cases or some crystallographic structures are not accurate 
Please tell me that if you find any paper on test a scoring functions using 
of PDB entries.

Please sent comments to chen_jianquan at yahoo.com or visit 
http://www20.brinkster.com/jianquan/aedock11/default.asp or my homepage

Note:(1) some contents are extracted from 
"Large-scale virtual screening for discovering leads in the postgenomic 
Waszkowycz, B.; Perkins, T. D. J.; Sykes, R. A.; Li, J. . IBM SYSTEMS 
2001, 40, 360-376.

(2) please include the web address of this paper 
and my name if you want to cite the opinions in this paper.

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