Insilico Studies on Anticancer Compounds: Targeting the Cell Cycle
IR@IICB: CSIR-Indian Institute of Chemical Biology, KolkataView Archive Info
Insilico Studies on Anticancer
Compounds: Targeting the Cell Cycle
Manuel Mascarenhas, Nahren
Structural Biology & Bioinformatics
In human, cell cycle is a tightly regulated event resulting in new cells.
Malfunctioning of such precisely controlled machinery could lead to uncontrolled
cell proliferation resulting in a class of diseases, known as cancer. Cancer is one of
the leading causes of death worldwide. Many key enzymes, which play pivotal
roles in cell cycle, are being targeted to develop new potent drugs for treating
cancer. Cyclin-dependent kinases (CDKs) belong to one such family of kinases that
have been under intense research, owing to their direct involvement in cell cycle
and cancer. This thesis employs ligand-based as well as structure-based approaches
to evolve novel efficient protocol for virtual screening and for understanding
protein-ligand interactions in two bona fide targets, CDK2 and CDK4, to design
selective inhibitors for treating cancer.
The first chapter of the thesis deals with the introduction to cell cycle, CDKs
and cancer. The various control mechanisms of CDKs are briefly discussed in this
section of the thesis. The relation between cancer and CDKs and why these are
considered as potent targets for cancer are also explained. The second chapter
briefly introduces the computational concepts and various in-silico methodologies,
used in this thesis work (Chapter 1 & 2).
The structure of CDK2 is well established, hence a structure based
pharmacophore was developed based on the X-ray structures of CDK2 complexed
with three derivatives of 3-aminopyrazoles (PDB ID: 2BPM, 1VYZ, 1VYW). The
feature-shape defined in the pharmacophore was used to align molecules to perform
3D-QSAR studies as well as to extract hits by screening conformational databases.
The 3D-QSAR was validated and checked for internal consistency as well as for its
predictive ability. The model was able to distinguish the activities of enantiomers as
well. A rigid docking approach was utilized to place the molecules into the active
site of CDK2. A consensus scoring method was applied to predict the protein-ligand
affinity and to predict the affinity of hits obtained. As an outcome of the study a
novel protocol for virtual screening has been evolved which identified some
In the second study, 2D-QSAR studies have been performed on a series of
pyrido[2,3-d]pyrimidin-7-ones, followed by docking on a homology model of
CDK4, generated under the same study. A fragment based QSAR methodology was
adopted to understand the structure-activity relationship for this system. To
formulate easily interpretable models that could guide a medicinal chemist, only
those descriptors that offer a direct physicochemical interpretation have been used.
In all, five QSAR equations were developed by different combination of descriptors
and statistical methods. The docking studies enhanced further the understanding of
structure-activity relationship of these inhibitors as well as identified the binding
mode of this subset of inhibitors towards CDK4
A molecular dynamics study has been carried out to investigate the
selectivity aspect of lig17 (6-Bromo-8-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-
ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one) towards CDK4 as against CDK2. The
positive charge on the ligand was favourably contributing towards its binding in
CDK4. On the other hand, the presence of Lys89CDK2 creates a significant strain in
CDK2-17 complex affecting the conformation of lig17 and hydrogen bonding
interactions with hinge residues. The pyridine nitrogen was found to interact with
CDK4 through a hydrogen bonding interaction with His95. It also exhibited
significant water-mediated interactions with hinge residues. The G-loop of CDK4
was found to be highly mobile when complexed with lig17. The Tyr17CDK4/CDK4-17
residue was found to flip out of the G-loop to get exposed to the solvent. Principal
component analysis (PCA) was also performed to extract functionally relevant
motions of the two proteins.
Manuel Mascarenhas, Nahren (2010) Insilico Studies on Anticancer Compounds: Targeting the Cell Cycle. PhD thesis, Jadavpur University.