Subject: Abstracts of papers at ACS - Pharmacophore Symposium

From: "Osman F. Guner" <[email-masked]>
Date: Wed, 30 Dec 1998 08:20:58 -0800

TUESDAY AFTERNOON 
Section A 
Techniques in Pharmacophore Development 1
O. Güner, Organizer, Presiding

1:30*45. What makes a good pharmacophore? E. Abrahamian, S. L. Chan, R. D.
Clark, T. W. Heritage 
An experienced molecular modeler can often look at a particular
pharmacophore-based query and know whether it is likely to produce useful
results when used to carry out a 3D search - i.e., whether it will be so
general that it "hits" too many structures, or so specific that it "hits" too
few.  The recent introduction of partial match capabilities in commercial 3D
searching packages has rendered such evaluation considerably more difficult,
but it is still humanly possible.  In carrying out recent work on automated
pharmacophore hypothesis generation, it became clear that a priori evaluation
of the information content and/or discrimination power of a 3D query is in
fact
quite a complex task.  Nonetheless, certain general relationships do exist
between query structure and information content which can allow quantitative
analysis which goes beyond simple rules of thumb.  Results of such analyses
will be presented.

2:00*46. Automatic pharmacophore generation using catalyst. J. Sutter, O.
Güner, R. Hoffman, H. Li, M. Waldman 
Catalyst is a program suite that automatically generates pharmacophores using
only experimentally-obtainable ligand information;  2D structure and
biological
activity.  Catalyst calculates a conformational model for each molecule,
creates initial pharmacophores that are common among the active compounds but
not among the inactive compounds, and optimizes the pharmacophores using
simulated annealing.  Each pharmacophore is scored using a cost function that
accounts for its complexity, the deviation from ideal chemical weights for
each
chemical feature, and the differences between the predicted and measured
activities.  The pharmacophores can be used to predict the activity of unknown
compounds or to search for new possible leads contained in 3D chemical
databases.  In this presentation, validation studies involving new
developments
in Catalyst including the use of variable weights and tolerances will be
discussed.

2:30*47. Evaluation of automated methods for pharmacophore model
generation. K.
Gundertofte, B. Bjørnholm, M. Langgård 
A pharmacophore model of the serotonin reuptake site has been developed using
classical pharmacophore modelling tools.1 The model can explain
enantioselectivity as well as selectivity towards norepinephrine and has been
validated against several test compounds.
Newer, automated techniques for pharmacophore model generation, Catalyst,
Cerius2 and Flo96 have been applied on the serotonin reuptake site. The
generated pharmacophore models have been compared to our classical model.
Differences in performance of the applied methods will be discussed.
Reference1:  Gundertofte, K., Bøgesø, K.P. and Liljefors, T., A
Stereoselective
Pharmacophoric Model of the Serotonin Reuptake Site. In H. van de Waterbeemd,
B. Testra and G. Folkers (Eds.), Computer-Assisted Lead Finding and
Optimization.  WILEY-VCH, Weinheim, 1997, pp. 443-459.

3:00*48. Substrate mapping through a multiple copy simultaneous search : a new
methodology applied to peptide deformylase. L. Patiny 
The multiple copy simultaneous search method (MCSS) was developed by
Karplus in
order to create functionality maps of binding sites for proteins having a
known
catalytic site.
In this communication we would like to present the use of the MCSS in order to
quickly determine the position of a catalytic site knowing a substrate and the
structure of the protein. In order to reach this goal we are using directly
the
substrate in the minimisation. To circumvent the difficulties linked to the
degree of freedom, the substrate is reduced, in a first step, to 50%. After
the
MCSS, we let the substrate inflate in the protein.
We will present results that was obtained on peptide deformylase and compare
them to experimental results.

3:30*49. Exploiting pharmacophores using oracle. K. Davies, R. Ponstance
The 3D pharmacophore searching technology developed by Chemical Design in the
early 1990s was adapted to provide a quantitative measure of pharmacophore
diversity for Combinatorial Chemistry Library Design.  This used the concepts
of pharmacophore fingerprints or keys which have also been used to identify
pharmacophores which may be associated with activity.  Recent advances in
computer speed and the falling costs of diskspace, have allowed the
pharmacophores for individual molecules to be stored in an ORACLE database. 
This enables much more rapid development and testing of hypothesis for the
pharmacophore responsible for a given activity which in turn may significantly
reduce the time taken for lead explosion and lead optimisation.  This paper
includes examples using this technology to select molecules to exhibit a
desired selectivity of biological response.

WEDNESDAY MORNING 
Section A 
Techniques in Pharmacophore Development 2 
NEW ALGORITHMS IN PHARMACOPHORE DEVELOPMENT 
O. Güner, Organizer, Presiding

8:30*57. Field-based similarity forcing: a conformationally-flexible approach
to pharmacophore perception. J. R. Blinn, G. M. Maggiora, D. C. Rohrer 
A new molecular field-based similarity forcing method for matching
conformationally flexible molecules is presented.  The method extends earlier
work on field-based similarity matching of molecules based upon the MIMIC
program, by directly coupling the similarity matching function to a molecular
mechanics force-field.  Thus conformational energetics are now fully accounted
for within the similarity-matching process, and conformational searching
constrained by the similarity function ('similarity forcing') can be carried
out concurrently.  This method is quite similar to that used in NMR-based
structure determination with NOE distance constraints.  Although a Monte Carlo
search procedure is used in the present work, any type of search procedure can
be employed.  After the best matchings have been determined, a series of post
matching analyses are performed to obtain information on the underlying
pharmacophoric patterns.  These analyses included an evaluation of appropriate
similarity fields and inter-molecular atom-atom similarities.  An example from
several HIV-1 RT inhibitors will be presented to illustrate the salient
features of the method.

9:00*58. Extraction of the maximum 3d common substructure from a set of
ligands. J. Gasteiger, S. Handschuh, M. Wagener 
Ligands binding to the same receptor are superimposed in order to extract the
essential three-dimensional structure necessary for ligand binding. In this
process, geometry changes due to conformational flexibility are explored to
maximize overlap. The entire process uses a combination of a genetic algorithm
with a quasi-Newton optimizer. The method can be applied to a set of ligands
even if the 3D structure of the receptor is not known, and to hits from
high-throughput screening.

9:30*59. Vector and tensor pharmacophores from quantum mechanical
calculations.
T. Clark, M. Hennemann, B. Martin 
The detailed electrostatic and polarizability information available from even
very simple (in this case AM1 semiempirical MO) quantum mechanical
calculations
can be converted into hydrogen bonding vectors, linear quadrupoles for
aromatic
ring binding sites and group polarizability tensors to characterize lipophilic
groups. The spatial relationships between the different sorts of binding site
on the molecule can be used to derive 3D-pharmacophores both from limited
(20-50 compound) activity data and from larger numbers of compounds that have
been identified to be active. The pharmacophore models thus derived can be
used
to scan entire 3D-databases at a speed of about 2,500 molecules per processor
minute to obtain quantitative estimates of individual activities. Examples of
the results of such searches will be presented.

10:00*60. The concept of pharmacophore and anti-pharmacophore shielding in
drug
design and structure-property relationships. I. B. Bersuker, S. Bahceci, J. E.
Boggs, R. S. Pearlman 
The widely employed concept of Pharmacophore (Pha) is complemented by the
notions of Basic Skeleton (BS) and Anti-Pharmacophore Shielding (APS). The Pha
is assumed to be the necessary element that produces the activity under
consideration, while the BS is formed by adding to the Pha maximum possible
atomic groups that do not influence the activity (they fill the cavities in
the
ligand-receptor interaction), and the APS is defined as additional (to the BS)
groups that hinder the proper Pha-receptor docking, thereby diminishing
(partially or completely) the activity. In combination with our
Electron-Conformational method of pharmacophore identification, suggested
earlier, the concept of BS and APS simplifies the search for Pha and allows
for
approximate numerical predictions of activities. These computer implemented
novel ideas are applied to two problems: rice blast activity and
angiotensin-converting enzyme inhibitors.

10:30*61. Advanced pharmacophore keys. S. J. Cato
Chem-X software allows study of the potential pharmacophores exhibited by a
collection of molecules and expresses the results as pharmacophoric
fingerprint, called a pharmacophore key.  It recognizes up to seven types of
interaction centers automatically and finds all possible permutations of three
of these as potential pharmacophores in each low energy conformation, setting
the appropriate bits in the key.  This paper compares and contrasts two
extensions to the standard pharmacophore keys.  The use of four-center
pharmacophores (rather than three), allows the pharmacophores found to be
space
filling (rather than planar) and creates a much larger potential pharmacophore
space.  Alternatively, 'profiling', allows a count of the pharmacophores (as
opposed to single bits of each) to be stored in the key on either a molecular
or conformational counting basis.  The application to the diversity comparison
of libraries and diverse subset selection is examined.

WEDNESDAY AFTERNOON 
Section A 
Techniques in Pharmacophore Development 3 
New Approaches: PHARMACOPHORES FROM RECEPTOR ACTIVE SITES
O. Güner, Organizer, Presiding

1:30*62. Genefold: protein sequence to structure to receptor pharmacophore. A.
Nayeem 
When a given protein sequence does not exhibit sufficient sequence identity to
known proteins, threading methods have often proven successful in identifying
protein folds most likely to be compatible with that sequence.  Here we
examine
how far we can go beyond fold recognition.  The application GeneFold, a
threading program developed by Godzik and Skolnick at Scripps, for
developing a
pharmacophore model for the binding site of an enzyme is shown.  The value of
the model as a basis for searching chemical libraries is also discussed.

2:00*63. Novel structure based approaches to pharmacophore model generation
and
library focusing. C. M. Venkatachalam, P. Kirchoff, J. Jiang, M. Waldman 
Given a library of compounds, the problem of identifying compounds that can
satisfactorily dock and interact with a known Protein active site, is a
challenging one. To be able to select potentially interesting compounds from a
library using known information about the three dimensional structure of the
active site is very crucial in generating leads especially when using
combinatorial libraries. We present two different but complementary
approaches:  One approach employs a fast docking algorithm that finds low
energy conformations of a ligand within an active site. The other approach
analyzes the active site to develop a set of features (such as hydrogen bond
donors, acceptors and lipophilic sites) that are required for attractive
interactions within the active site and uses the feature set to derive
pharmacophore models that are then employed in database searching to identify
hits.

2:30*64. Pharmacophores including multiple excluded volumes derived from x-ray
crystallographic target structures to be used in 3d-database searching. P. A.
Greenridge, M. Gilner 
We have optimised the method of using many (>100)  excluded volumes with
3D-pharmacopho-res in database searching with respect to specificity and speed
(J.Med.Chem. 41:2503-2512, 1998). Structure-based pharmacophores were
supplemented with exluded volumes positioned at the coordinates of the protein
atoms delineating the ligand binding site. The search speed obtained makes it
practically feasible to use this method, and significantly faster than
reported
for other softwares. The method effectively pruned the obtained hit-lists of
unspecific hits (by 70-75%) . Experimental verification showed that the
remaining hits were specific (had micromolar affinities). We now show for
structure-based pharmacophores that this method also improves the correlation
between predicted and measured affinities for a structurally diverse set of
estrogen receptor ligands. The resulting regression equation may be used for
scoring of database hits.

3:00*65. Docking - derived pharmacophores. R. Griffith, J. B. Bremner, B.
Coban

In the absence of any detailed 3D structure of adrenergic receptors, models
have been constructed for the alpha1A and alpha1B subtypes of these important
members of the G-protein coupled family of membrane-bound receptors.
Docking of
the endogenous ligand, adrenaline, and also of a rigid, alpha1A selective
antagonist (IQC), developed in our laboratory, into these models will be
presented. We have, in a novel application of the Catalyst software by MSI,
constructed docking derived pharmacophores from the docking results. These
will
be presented, as well as comparisons with traditional, ligand based
pharmacophores, which were developed in Catalyst using a set of subtype
selective antagonists, not including IQC. The common features of "ligand" and
"structure" based pharmacophores can be superimposed strikingly well. This new
approach offers further opportunities for tailored ligand design.

3:30*66. A dynamic pharmacophore model for HIV-1 integrase. H. A. Carlson, K.
M. Masukawa, R. D. Lins, J. M. Briggs, W. L. Jorgensen, J. A. McCammon 
50-ps snapshots of a 1-ns molecular dynamics simulation of the catalytic
domain
of HIV-1 Integrase were used to represent the conformational flexibility
inherent to the active site.  Each of these protein configurations was
subjected to a Multi-Unit Search for Interacting Conformers (MUSIC) simulation
(a Monte Carlo, multiple-copy method available in the BOSS program).  The
MUSIC
studies were used to develop a dynamic pharmacophore model based on the
sampling of conserved binding sites for hydroxyl and ammonium functionalities
in the active site of each protein model.  The use of this method was
validated
by accurately predicting the binding site for the first of two required
magnesium ions.  Variations of our pharmacophore model were used to search the
Available Chemicals Database.

4:00*67. Pharmacophore definition of retinoid-x-receptor modulators. S. K.
White
The Retinoid-X-Receptors (RXR) are homodimer and heterodimeric partners with a
variety of intraceullular receptors, including PPAR, TR and VitD. While high
affinity binding to the RXR's is important, we use a funtional cotransfection
assay to differentiate the role of the RXR ligand. The criteria for good
structure-activity correlation depends on proper choice of ligands
according to
biological function, pharmacophore sampling and 2D similarity. A general
method
of selecting ligands via biological activity profile and 2D descriptors for
training sets in pharmacophore analysis will be presented. By using 2D
chemical
structure information to bin our ligands, we are able to create 3D
pharmacophore descriptions which correlate to the activity data with R2 >
0.90.

--
Osman F. Güner, Ph.D.
Sr.Product Manager,    Rational Drug Design
Molecular Simulations Inc.  (619)799-5341
[email-masked]            http://www.msi.com