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Insilico Studies on Anticancer Compounds: Targeting the Cell Cycle

IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata

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Title Insilico Studies on Anticancer Compounds: Targeting the Cell Cycle
Creator Manuel Mascarenhas, Nahren
Subject Structural Biology & Bioinformatics
Description 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 potential leads 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.
Date 2010
Type Thesis
Format application/pdf
Identifier http://www.eprints.iicb.res.in/495/1/MAIN_TEXT.pdf
Manuel Mascarenhas, Nahren (2010) Insilico Studies on Anticancer Compounds: Targeting the Cell Cycle. PhD thesis, Jadavpur University.
Relation http://www.eprints.iicb.res.in/495/