CCL: W:Computational drug design blues
- From: "Phil Hultin" <hultin=-=cc.umanitoba.ca>
- Subject: CCL: W:Computational drug design blues
- Date: Wed, 14 Sep 2005 09:40:53 -0500
Sent to CCL by: "Phil Hultin" [hultin=-=cc.umanitoba.ca]
This question about the synthetic feasibility of a computationally-selected
drug candidate is a very good one, but unfortunately there is not a nice
To decide whether a structure is synthetically accessible, the only way that
I can think of is to actually know organic chemistry. It is usually pretty
straightforward to identify things that are "hard" to make based on
relatively elementary knowledge of reactions. It is NOT straightforward to
decide whether something is "easy" to make, however - at least not for
molecules of any complexity.
I would suggest that any computational drug designer should consider a
refresher course in organic chemistry, followed by a basic introduction to
the design of organic syntheses such as Stuart Warren's book "Organic
Synthesis: the disconnection approach".
In a computation, we generally believe that things are deterministic and
thus that a single result (within round-off error) should be obtained from a
fixed starting point. In synthesis, there is no single answer to the
question of how to synthesize a given target. Moreover, the number of
permutations grows exponentially (at least) as the size of the target grows.
Thus, there is a qualitative element to determining whether something is
feasible or not.
Of course, I am quite aware that there is a qualitative and creative element
to computational chemistry too and I do not mean to put down computational
people in any way, or to set organickers up on a pedestal.
Dr. Philip G. Hultin
Associate Professor of Chemistry,
University of Manitoba
> From: owner-chemistry=-=ccl.net [mailto:owner-chemistry=-=ccl.net]
Sent: September 14, 2005 9:10 AM
To: Hultin, Philip G.
Subject: CCL: W:Computational drug design blues
Sent to CCL by: "Sandeep Kumar" [kumarsan\a/jhu.edu]
I need some advice about the drug discovery/design. Using structure based
design, one could develope several potential small molecular
inhibitors/drugs for a given protein target. Many of these compounds may
appear very attractive as they satisfy all lipinski's rules and your
requirements for selectivity/specificity and may even have desirable
solubility/ADME profiles. These days its possible to incorporate all these
features right at the computational design stage. However, the organic
synthesis of the compound still remains a bottleneck as it turns out that
many of the designed compounds are 'hard' to synthesize or may require many
steps of synthesis. I was wondering if there are some simple guidelines in
the form of literature or 'hands on' experience available which could tell
the computational/medicinal chemist whether a designed compound would be
easy or hard to synthesize before he/she talks to the organic chemist.
All your responses are greatly appreciated.
Sandeep Kumar, Ph.D.
Johns Hopkins University,
Dept. of Biology,
106 Mudd Hall,
3400 N. Charles St.
Baltimore, MD 21218.