Anticancer Drug Design: Development of Cyclin-Dependent Kinase Inhibitors Using In Silico Techniques (original) (raw)
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Molecular Docking and Qsar Studies on CDK4 Inhibitors Using in Silico Techniques
Journal of Pharmaceutical & Scientific Innovation, 2014
Cyclin-dependent kinases are a small family of serine/threonine protein kinases which control the cell cycle progression. Literature survey revealed that CDKs, their regulators, and substrates are the targets of genetic alteration in many human cancers. The best characterized case of such alteration is the p16-CDK4, 6/cyclin D-retinoblastoma pathway found in more than half of all human cancers. Therefore, CDK4 is an attractive target for the development of a novel anticancer agent. Computer aided drug design strategy has gained much prominence due to the fast and efficient means of studying protein-ligand interactions. A molecular docking was performed using Molegro Virtual Docker 6.0 with the CDK4 protein and the selected compounds from literature as ligands. QSAR toxicity analysis has been performed using FAF Drugs ADME/tox filtering server. Considering the molecular properties of the ligands, higher inhibitory activity is associated with reduced molecular flexibility, as measured by lower polar surface area (TPSA), LogP, lower hydrogen bond counts, confirming the capability of the compounds for binding at the active site of the receptor.
Fusion of Structure and Ligand based methods for identification of novel CDK2 Inhibitors
Journal of chemical information and modeling, 2017
Cyclin dependent kinases plays a central role in cell cycle regulation which makes them a promising target with multifarious therapeutic potential. CDK2 regulates various events of the eukaryotic cell division cycle and the pharmacological evidences indicated that over expression of CDK2 causes abnormal cell-cycle regulation, which was directly associated with hyper proliferation of cancer cells. Therefore, CDK2 is regarded as a potential target molecule for anti-cancer medication. Thus to decline CDK2 activity by potential lead compounds has proved to be an effective treatment for cancer. The availability of a large number of X-ray crystal structures and known inhibitors of CDK2 provides a gateway to perform computational studies on this target. With the aim to identify new chemical entities from commercial libraries with increased inhibitory potency for CDK2, ligand and structure based computational drug designing approaches were applied. A drug like library of 50,000 compounds fr...
Structural Bioinformatics Approach of Cyclin-Dependent Kinases 1 and 3 Complexed with Inhibitors
Molecular Informatics, 2011
The cyclin-dependent kinases or CDKs participate in the regulation of both the cell progression cycle and the RNA polymerase-II transcription cycle. In several human tumours deregulation of CDK-related mechanisms have been detected, e.g., overexpression of cyclins or deletion of genes encoding for CKIs. Regarding these observations, CDKs came up to be interesting targets for elaboration of novel antitumour drugs. Based on the importance of the CDKs, this research aimed to describe, to characterize and to compare the molecular models of CDK1 and CDK3. Since the structures of human CDK1 and CDK3 are unavailable in the Protein Data Bank -PDB, homology models were created based on the CDK2 as the template, once they share a substantial identity. The structural studies of the CDK1 and CDK3 biding sites were conducted by molecular docking with 15 different CDK inhibitors previously identified to CDK2. This study allowed the understanding of the structure of the complexes between CDK1/ CDK3 with inhibitors. The knowledge of their structural features mainly the biding sites might be useful to discovery and rationalization of drug design process.
Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy
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Cyclin-dependent kinase 2 (CDK2) is an essential protein kinase involved in the cell cycle regulation. The abnormal activity of CDK2 is associated with cancer progression and metastasis. Here, we have performed structure-based virtual screening of the PubChem database to identify potent CDK2 inhibitors. First, we retrieved all compounds from the PubChem database having at least 90% structural similarity with the known CDK2 inhibitors. The selected compounds were subjected to structure-based molecular docking studies to investigate their pattern of interaction and estimate their binding affinities with CDK2. Selected compounds were further filtered out based on their physicochemical and ADMET properties. Detailed interaction analysis revealed that selected compounds interact with the functionally important residues of the active site pocket of CDK2. All-atom molecular dynamics simulation was performed to evaluate conformational changes, stability and the interaction mechanism of CDK2...
In silico design of small molecule inhibitors of CDK9/cyclin T1 interaction
Journal of Molecular Graphics and Modelling, 2014
In order to design a small molecule which potentially may interfere with CDK9/cyclin T1 complex formation and therefore influence its physiological role, a computational study of dynamics and druggability of CDK9 binding surface was conducted. Druggability estimates and pocket opening analyses indicated binding regions of cyclin T1 residues, Phe 146 and Lys 6, as starting points for the design of small molecules with the potential to inhibit the CDK9/cyclin T1 association. A pharmacophore model was created, based on these two residues and used to select potential inhibitor structures. Binding energies of the inhibitors were estimated with MM-GBSA. A good correlation of MM-GBSA energies and FTMap druggability predictions was observed. Amongst studied compounds a derivative of 2-amino-8-hydroxyquinoline was identified as the best potential candidate to inhibit CDK9/cyclin T1 interactions.
Identification of Novel CDK Inhibitors by Molecular Docking and Consensus Scoring Approach
International Journal of Computer Applications, 2015
Cyclin Dependent Kinases go about as potential remedial focuses in cancer disease and several efforts are under way to find out more specific, potent and selective CDK inhibitors. In this paper, reported a computational molecular docking approach to screen approved drugs from DrugBank database. Docking and scoring of all compounds was done using Molegro Virtual Docker software, evaluated the binding affinities towards CDK-2, 4, 5 and 9 enzymes 2W9F, 2UZO, 1UNH and 3BLR resulted in variable dock scores. The resultant top 14 hits from a dataset of 1584 approved drugs were found to be more specific towards CDK inhibition. Further, re-scoring of 14 best docked poses followed by a consensus scoring approach retrieved top hits. In this study, tested three different scoring functions such as MolDock score of Molegro software, GOLD score and AutoDock. From the analysis, it was observed that Olmesartan and Telmisartan were reported to have high binding affinities with all CDKs tested.
Cyclin-dependent kinase 1 (CDK1) is a valid anticancer target. With this in mind we applied a modeling workflow by combining pharmacophore modeling and QSAR analysis followed by in silico screening towards the discovery of novel inhibitory CDK1 scaffolds. Virtual screening identified 10 low micromolar inhibitory leads: 8 from the National Caner Institute (NCI) list of compounds and 2 from our in house list of established drugs and agrochemicals. The most potent NCI hit illustrated anti-CDK1 IC 50 value of 0.83 mM, while the drug hit isoxsuprine illustrated anti-CDK1 IC 50 value of 2.9 mM and the agrochemical hit foramsulfuran showed IC 50 ¼ 3.6 mM. These results demonstrate that our virtual screening protocol is able to identify novel anti-CDK1 leads for subsequent development into potential anticancer agents.
Structure‐guided discovery of cyclin‐dependent kinase inhibitors
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CDK2 inhibitors containing the related bicyclic heterocycles pyrazolopyrimidines and imidazopyrazines were discovered through high-throughput screening. Crystal structures of inhibitors with these bicyclic cores and two more related ones show that all but one have a common binding ...
An in silico evaluation of CDK Inhibitors targeting BCL2, TS and mTOR
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The cyclin dependent kinase (CDK) inhibitors have recently been found to be of potential use as anticancer drugs. The present research work focuses on screening of compounds targeting multiple pathways involved in human cancers along with CDK-regulated cell cycle for prospective anticancer potential. Molecular docking study of selected compounds were performed to determine the binding affinity of selected compounds towards respective targets of cancer cells to verify if there is any physical interaction of these inhibitors with their reported target proteins as claimed in the existing literatures. Prior to docking, molecular pathway prediction and gene set enrichment analyses were performed to identify the target molecules by using appropriate bioinformatics tools. Interestingly, the results of in silico molecular docking have been found to be in line with the laboratory findings that are obtained from the literatures. Specifically, few of our selected CDK inhibitors, namely Abemaciclib, Palbociclib, AMG 925 and RGB 286638 showed good binding scores against BCL2, TS, mTOR in addition to CDKs (4, 6 and 9). On the basis of scientific evidence based on published scholarly articles and according to molecular docking results, it can be inferred that these CDK inhibitors as anticancer agents may play a very promising role in cancer treatment and can be used as potential lead compounds for the development of target therapy against human cancers. However, more intensive research is needed to confirm the feasibility of these compounds to be used in treating cancer and it is expected that this work will provide a stimulating impetus for the development of chemotherapeutic agents in future.