Special Lecture as part of Advanced Course-cum-Workshop on
“Molecular Modelling and Protein-Ligand Interactions”
On 14 December 2007 at 10:15 a.m.
In Ground Floor Lecture Hall
NCBS (TIFR)
Modelling pentraxins and inferring ligand specificities
Prof. N. Srinivasan
Molecular Biophysics Unit
Indian Institute of Science
Bangalore 560012
The family of pentraxins consists of Serum amyloid P-component (SAP) which is related
to Alzheimer's and amyloidosis and C-reactive protein (CRP) which is an acute phase
response protein. Though the homologous members of pentraxin family are closely
related they elicit differences in ligand specificities and in oligomeric states. Using
comparative modeling of pentraxins on the basis of the 3-D structure of human SAP,
some years ago, we explained ligand specificity differences between SAP and CRP.
While phosphocholine could bind to CRP, it is unable to bind to SAP. Using
phosphoethanolamine-bound form of SAP crystal structure we could pin-point residuedeterminants in CRP that facilitates phosphocholine binding. We also used the
pentameric SAP structure in explaining how Limulus CRP could form a hexamer. We
will also outline the nature and extent of functional drifts within homologous enzyme
domain families.
Special Lecture as part of Advanced Course-cum-Workshop on
“Molecular Modelling and Protein-Ligand Interactions”
On 15 December 2007 at 10:15 a.m.
In Ground Floor Lecture Hall
NCBS (TIFR)
Protein –Ligand structural studies for design of GSK3-β in 16 hibitors
Dr. V. N. Balaji*, Ph.D.,
Director and Chief Scientific Officer,
Jubilant Biosys Limited+, #96, Industrial suburb,
2nd Stage, Yeshwanthpur, Bengalooru, Karnataka 560 022, INDIA
Abstract:
Inhibitor design for proteins of therapeutic importance is a key step in drug discovery.
Glycogen Synthase Kinase 3-β (GSK3-β) is an important protein which plays a role in
the signaling pathways of several human diseases. Discovery and inhibitor design of
GSK3-β is of therapeutic importance. In the present talk we illustrate the methods
adopted for design of GSK3β inhibitor. We have conducted analysis of the X-ray
structures of GSK3-β with different ligands to understand the mobility of binding sites.
We present molecular docking studies of ligands with several X-ray crystal structures and
induced fit models of the same. Using the docking GlideScore (Schrodinger docking
tool) as the ranking metric, we have computed the enrichment of known GSK3-β
inhibitors which are seeded in a decoy set of World Drug Index (WDI) compounds.
Interestingly, our studies find that extra precision docking of compounds into the
ensemble of protein structures either from X-ray crystal structure data or induced fit
models or by ranking them led to the best retrieval of actives in the top 5% and 10% of
the database with significant enrichment. Our studies highlight the significance of
induced fit models in such enrichment when experimental data is limited. These studies
provide valuable insights into strategies useful for the prioritization of molecules for
synthesis and evaluation towards discovery of potential GSK3β inhibitors.
[References: P.K. Gadakar, S. Phukan, P. Dattatreya & V.N. Balaji; Pose Prediction
Accuracy in Docking Studies and Enrichment of Actives in the Active site of GSK-3β, J.
Chem. Inf. Model. 2007, 47, 1446-1459. P.K. Gadakar, S. Phukan, P. Dattatreya & V.N.
Balaji Enrichment of Potent GSK-3β inhibitors from docking studies in the enzyme
active site. Current Science, 2007, 93, 1100-1107. S. Phukan, H. Rajesh, N. Malini &
V.N. Balaji; Analysis of crystal structures of GSK3-β and its ligand binding domain.
(Unpublished results).]
*(vnbalaji@jubilantbiosys.com).
+(www.jubilantbiosys.com)
Special Lecture as part of Advanced Course-cum-Workshop on
“Molecular Modelling and Protein-Ligand Interactions”
On 17 December 2007 at 9 a.m.
In Ground Floor Lecture Hall
NCBS (TIFR)
Characterization of molecular recognition: Protein-ligand interfaces
Dr. Nagasuma Chandra
Bioinformatics Centre and Supercomputer Education and Research Centre
Indian Institute of Science, Bangalore
Molecular recognition events drive all biological processes. Protein-ligand interactions
are key determinants of biochemical reactivity and hence their understanding is crucial
for understanding the function of the protein and of the biological process. In this talk,
substrate and inhibitor binding to phosphoglycerate kinase, an important glycolytic
enzyme, using a combination of X-ray crystallography, NMR and molecular modeling
methods will be discussed. Molecular modelling and electrostatic calculations suggested
the location of the triose phosphate binding site and further that the protein would
undergo a large hinge bending motion to facilitate catalysis, which were further
confirmed by crystallographic studies.
A new method, PocketDepth, was developed in our laboratory for the prediction of
binding sites in protein structures, serving as a first step to characterize protein-ligand
interfaces. Determinants of ligand recognition in chosen classes of proteins followed by
mining common patterns at the interfaces in a diverse set of proteins with common
function, will be presented.Special Lecture as part of Advanced Course-cum-
Workshop on “Molecular Modelling and Protein-Ligand Interactions”
On 18 December 2007 at 10:15 a.m.
In Ground Floor Lecture Hall
NCBS (TIFR)
Assessment of Protein Druggability by Structural Means
Dr. Kothandaraman Seshadri
ASTRA Zeneca
Bangalore
Abstract
Identification of a target system that can be suitably controlled with a drug molecule is
the first important step in the drug discovery process. Majority of drug targets are protein
molecules and the drug molecules usually bind to their well-defined cavities. Such drug
binding sites should have certain sequence, structural and physiochemical properties to
accommodate high affinity, site-specific binding and subsequent regulation of protein
activity by drug like molecules. Characterization of these binding sites may give some
useful insights about the properties of the protein pockets that favour binding of drug like
molecules. Recently there has been a surge of interest in this area. Ingredients that go into
making a successful assessment of protein druggability based on computationally
obtained properties, from recent literature would be discussed.