Computational Studies On The Inhibitory Mechanism Of Targeted Anticancer Drugs And Molecular Design

Cancer is defined as a desease which is corrected with the defective DNA damage response (DDR). Increasing knowledge of critical cell signals in many malignances brought about the emerging era of targeted therapy. By often targeting more specific, upregulated and mutated signaling pathways, the pharmacological inhibition of oncogenic kinases represents a treatment option for cancer. Identification of potent inhibitors targeting oncogenic kinases may have a substantial therapeutic benefit. Computer-aided drug design techniques, as a rational approach to maximize the chances of finding new drugs and to exploit the opportunities of potential new drug targets, can now be effective in reducing costs and speeding up anticancer drug discovery.In Chapter 1, we highlighted that the initiation and growth of tumor was directly related to the disruption of the mechanisms that regulate cell-cycle, DNA repair, and apoptosis, with the main emphasis on critical analysis of the classification and the structures of the oncogenic kinases. A detailed description of kinase inhibitors was also presented, including the classification and the challenges of the inhibitors. Furthermore, a short introduction of the procedure followed by the drug discovery process was also given, shedding light on the importance of computer-aided drug design techniques.Chk1, a serine/threonine protein kinase that participates in transducing DNA damage signals, is an attractive target due to its involvement in tumor initiation and progression. As novel Chkl inhibitors, the triazolone’s bioactivity mechanism is not clear. In Chapter 2, we carried out an integrated computational study that combines molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations to identify the key factors necessary for the bioactivities. With the aim of discerning the structural features that affect the inhibitory activity of triazolones, MK-8776, a Chkl inhibitor that reached clinical stage, was also used as a reference for simulations. A comparative analysis of the triazolone inhibitors at the molecular level offers valuable insight regarding the structural and energetic properties. A general features is that all the studied inhibitors bind in the pocket characterized by residues Leul4, Val22, Ala35, Glu84, Tyr85, Cys86, and Leu136 of Chkl. Moreover, introducing hydrophobic groups into triazolone inhibitors is favorable for binding to Chkl, which is corroborated by residue Leu136 with relatively large difference of the contribution between MK-8776 and five triazolones to the total binding free energies. A hydrogen bond between the polar hydrogen atoms at R1 and Cys86 can facilitate a proper placement of the inhibitor into the binding pocket of Chkl that favors binding. However, the introduction of hydrophilic groups to the R2 position diminishes binding affinity. The information provided by this research is benefit for the further rational design of novel promising inhibitors of Chkl.Flavones, which belong to the large group of flavonoids, have attracted much attention in relation to the therapeutic potential. Recently, this series of compounds have been shown to inhibit CK2 with outstanding efficiency and safety. However, the exact binding modes between CK2 and flavones, as well as the basis of their effects on the biological activities, remain yet unclear. In Chapter 3, we report the detailed account of the interactions between CK2 and flavones on the atomic level through computational approaches. Starting from four different molecular docking protocols, we obtained the relatively reliable initial complex structures by comparing docking scores. With subsequent molecular dynamic simulations and binding free energy calculations and decompositions, we found that the predicted binding free energies correlated well with pICso (R=0.86), shedding light on the necessity of MD studies. Meanwhile, the results clearly confirmed that hydrophobic residues such as Va139, Va147, Ile60, Phe107, Asn112, Met157 and Ile168 were responsible for flavones binding and identified the key structural elements necessary for their bioactivities. Based on the structural and energetic features of receptor-ligand interaction mechanism, we designed a series of novel compounds and their higher inhibitory activities were confirmed by comprehensive modeling study. We expect that these findings could serve as a paradigm for facilitating the process of developing novel and more promising inhibitors targeting CK2.Protein kinase CK2 and PIM1 both belong to serine/threonine kinases and share a relatively similar ATP binding site, which suggests that a significant proportion of molecules can simultaneously inhibit both proteins. However, recent studies showed that two molecules structurally related displayed different inhibitory potency against CK2 and PIM1. The structural basis of different selectivity presented by the two inhibitors remains unclear. In Chapter 4, a systematic and combinational computational modeling was respectively performed on the four systems constructed by the two inhibitors and two proteins. By means of IFD protocol, we characterized initial binding patterns between the inhibitors and kinases which were then subjected to MD simulations, binding free energy calculations and decompositions. A comparative analysis at the molecular level could lead to a deeper understanding of ligand selectivity. Our calculations showed that the van der Waals interactions involving residues such as Val65/Ala33, Phel12/Leu88 and Val115/Pro91, were responsible for the higher selectivity for 1. The observation was supported by the evidence that Va165, Phel12 and Val115 in CK2 were more hydrophobic than the corresponding residues including Ala33, Leu88 and Pro91 in PIM1. Similarly, the energetic and structural analysis revealed that the electrostatic interactions contributed by residues Lys67/Lys35, Glu80/Glu57 and Asp174/Asp154 had a great impact on the selectivity for 2. This can be attributed to the presence of the triazolone ring in 2 that participated to form stronger H-bond interactions to PIM1 than CK2. The data acquired from the computational study could offer valuable insight regarding ligand selectivity.