Subject: Summary: metrics of molecular diversity

From: "Dimitris Agrafiotis" <[email-masked]>
Date: Thu, 23 Feb 1995 10:16:04 -0500

Here is my original posting and a summary of the responses I received
regarding metrics of molecular diversity. Thanks to all who responded, and
sorry for the rather long delay in posting the summary.

Ciao,

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From: "Dimitris Agrafiotis" <dimitris>
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Date: Fri, 6 Jan 1995 10:04:10 -0500
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Subject: CCL:metrics for molecular diversity
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I am looking for a review of all the metrics that have been used to measure
molecular diversity in multidimensional physicochemical space. I am not so
much interested in metrics of distance between two compounds such as
Minkowski indices etc, but rather indices that measure the diversity
exhibited by a particular set of chemical compounds. I would appreciate
any pointers to books/reviews/papers on that subject and will summarize
the results in a future note. Thanks for your help.

--
Dimitris K. Agrafiotis, PhD             | e-mail: [email-masked]
3-Dimensional Pharmaceuticals, Inc.     | tel:    (215) 222-8950
3700 Market Street                      | fax:    (215) 222-8960
Philadelphia, PA 19104

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Date: Fri, 6 Jan 95 15:46:56 -0800
From: [email-masked] (Moises Hassan)
Message-Id: <[email-masked]>
To: dimitris (Dimitris Agrafiotis)
Subject: Re: metrics for molecular diversity
Status: ORp

There is a recent review of molecular indices (topological,geometrical,
electronic, ...) in the context of QSAR/QSPR in:

Katritzky, Alan and Gordeeva, Ekaterina, J. Chem. Inf. Comput. Sci.
1993, 33, 835-857

I"m also very interested in the area of assessment of molecular
similarity/diversity. Perhaps we can establish contact and share
information

--

===================================================================
   Moises  Hassan,Ph.D.
   Life Sciences Business Unit

   Biosym Technologies, Inc. 		  Phone:  (619) 546-5314
   9685 Scranton Road			  Fax:    (619) 458-0136
   San Diego, CA  92121-2777              e-mail: [email-masked]
===================================================================

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Date: Mon, 09 Jan 1995 08:59:09 -0600 (CST)
From: [email-masked]
Subject: Re: CCL:metrics for molecular diversity
To: dimitris
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Status: ORp

Let me know what you hear.

My favorite, unpublished per se, is to calculate distances between Hbond
donors, acceptors, positively charged groups, and negatively charged groups;
detect the cliques in common; count how many unique cliques there are. Sorry,
I forgot to add "hydrophobic" groups, because they give shape. We are part way
to
being able to do this automatically, but have been diverted by more "practical"
things.

I'll see if I can dig up a place where I have published any of this.

Yvonne

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Date: Mon, 9 Jan 1995 10:12:19 -0500 (EST)
From: Norah Shemetulskis <[email-masked]>
Subject: Re: CCL:metrics for molecular diversity
To: Dimitris Agrafiotis <dimitris>
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Status: ORSp

Hi Dimitris,

I'd be interested in hearing about any work in this area.
In case you might find the most recently published work
out of Chiron useful see:

	Simon, R.J.; Martin, E. J.; Miller, S.M.; Zuckermann, R.N.; Moos, W.H.
Using Peptoid Libraries[Oligo N-Substituted Glycines] for Drug Discovery.
Tech Protein Chem. 1994, V, 533-539.

and

  	Zuckermann, R.N.;Martin E.J., Spellmeyer, D.C.;Stauber,
G.B.;Shoemaker, K.R.;Kerr, J.M.;Figliozzi, G.M.;Goff, D.A.;Siana, M.A.;
Simon, R.J.;Banville, S.C.;Brown, E.G.;Wang,L.;Richter,L.S.;Moos, W.H.
Discovery of Nanomolar Ligands for 7-Transmembrane G-Protein-
Coupled Receptors from a Diverse N-(Substituted)glycine Peptoid Library.
J. Med.Chem. 1994,37(17),2678-2685.

I'm not sure whether this reference will be much use to you, but just
in case here it is (its on D-Optimal design):

  Baroni,M.'Clementi, S.;Cruciani, G.;Kettanch-Wold,N.;Wold,S.
D-Optimal Designs in QSAR. Quant. Struct.-Act. Relat. 12, 225-231(1993).

Happy New Year,
Norah

Norah E. Shemetulskis
Biomolecular Structure and Drug Design
Parke-Davis Pharmaceutical Research Division
Warner Lambert Company
(313)998-3360
[email-masked]

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Date: Mon, 9 Jan 95 10:07:05 -0800
From: uunet.uu.net!chiremv!andromeda!martine (Eric Martin)
Message-Id: <9501091807.AA20290@andromeda>
To: uunet.uu.net!uunet!3dp.com!dimitris
Subject: CCL:metrics for molecular diversity
Status: ORSp

Hello Dimitris,

I am very interested in your summary of responses.  Although it is not
explicitly over a "multidimensional physicochemical space", I have used
a simple method to compare "substructural diversity" of sets of
compounds based on the Daylight database fingerprints.  The Daylight
fingerprint routines search through a molecular structure to find all
of its substructures of up to 7 bonds.  A hashing algorithm randomly
assigns each substructure to one bit in a 2048 bit string.  The number
of bits set by the union of all fingerprints from a set of compounds
is, thus, a measure of substructural diversity of that collection.
Since several substructures may be assigned at random to the same bit,
the number of fragments (f) required to set a given number of number of
bits (b) is approximately f=2048(ln(2048/(2048-b))).  Since my interest
is in screening for orally available drugs, I have also divided this
value by the average molecular weight of the set as a measure of
"diversity density", i.e. how many substructures are available packed
into small molecules.  I do not have a reference, but the work is in
review at J. Med. Chem.

Good luck, -Eric

Eric Martin
[email-masked]
4560 Horton St., Emeryville, CA 94608
(510)601-3306,  FAX (510)601-3360

-- 
Dimitris K. Agrafiotis, PhD             | e-mail: [email-masked]
3-Dimensional Pharmaceuticals, Inc.     | tel:    (215) 222-8950
3700 Market Street                      | fax:    (215) 222-8960
Philadelphia, PA 19104