Belgrade Institute of Science and Technology

Science and, Serbia

Belgrade Institute of Science and Technology

Science and, Serbia
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Mitrasinovic P.M.,Wakayama University | Mitrasinovic P.M.,Belgrade Institute of Science and Technology
Medicinal Chemistry | Year: 2014

In our previous study, a protein engineering approach, accounting for the effects of single point mutations of the binding site residues on the stability of 22 thiazolo[4,5-d]pyrimidines in complex with the intracellular kinase domain of EGFR (PDB ID: 1XKK), was established in a systematic manner to be an efficient strategy for the identification of anti-EGFR-related-cancer drug candidates. The inhibitory activities of two lignad molecules, 4-(7-(3-chloro-4-morpholinophenylamino)thiazolo[4,5-d]pyrimidin-2-ylamino) benzenesulfonamide and 4-(7-(4-morpholinophenylamino) thiazolo[4,5-d]pyrimidin- 2-ylamino)benzenesulfonamide, exhibited some sort of uniqueness. Regardless of a slight mutual structural difference between these two ligands in only a peripheral Cl atom, their inhibitory activities against EGFR appeared to be associated with two quite opposite structural bases respectively. Herein, the fundamental rationalization of the remarkable standpoint is elaborated using both molecular docking and molecular dynamics simulations. Consequently, a number of implications of vital importance for the successful structure-based design of prospective drugs against EGFR-related cancers are discussed. © 2014 Bentham Science Publishers.


Babu B.V.,Indian Institute of Technology Roorkee | Konduru N.K.,Indian Institute of Technology Roorkee | Nakanishi W.,Wakayama University | Hayashi S.,Wakayama University | And 3 more authors.
Anti-Cancer Agents in Medicinal Chemistry | Year: 2013

The potential of flavonoids to act as anti-tumor agents has been recognized but not fully understood because flavonoids are acting at several stages in cancer progression with distinct structure-function relationships. A whole family of structurally different flavonoids is herein described by reviewing some critical aspects of their pro-oxidant behavior in vitro/vivo and in cell systems by which they may work as antioxidants. Different classes of flavonoids (chalcones, flavones, isoflavones, flavanols, flavanones and anthocyanins) are synthetically mimicked using natural product structure-antioxidant activity relationships that are relevant for their enhanced function against cancer as well as severe inflammation conditions under which an increased oxidative stress is often implicated. In the context of the common mechanisms of flavonoid action, clinical data on benefits of flavonoids in fighting against cancer are discussed. A structural basis needed to improve antioxidant activity of these agents is elaborated in more detail. © 2013 Bentham Science Publishers.


Mitrasinovic P.M.,Wakayama University | Mitrasinovic P.M.,Belgrade Institute of Science and Technology
Current Radiopharmaceuticals | Year: 2013

Epidermal growth factor receptors (EGFRS) belong to the ErbB family of receptor tyrosine kinases (TKS). Based on the role of EGFR signaling pathway in malignant progression of various types of tumors, a growing interest in the use of EGFR-TK inhibitors as probes for molecular imaging of EGFR-overexpressing tumors via positron emission tomography (PET) and single photon emission computed tomography (SPECT) is being notable. On one side, such non-invasive and repetitive monitoring of the activity of EGFR at the kinase level is intended to provide a direct measure of EGFR occupancy and inhibition by EGFR-targeting drugs. On the other side, all oncologic imaging tracers are molecularly targeted radiopharmaceuticals, which are strongly dependent on the tumor biochemistry including increased metabolism, Hyperproliferation, angiogenesis, hypoxia, apoptosis, and specific tumor biomarkers (tumor specific antigens and tumor-specific receptors). The present article is an attempt to reconcile these two vital standpoints influencing the choice of appropriate radio labeled agents for PET and SPECT imaging aimed to support the development of a new generation of multi-targeted kinase inhibitors in the time ahead, because the routine accomplishment of drug selectivity for particular protein kinases is a substantial challenge. © 2013 Bentham Science Publishers.


Mitrasinovic P.M.,Belgrade Institute of Science and Technology
Current Drug Targets | Year: 2010

Since 2003, highly pathogenic H5N1 influenza viruses have been the cause of large-scale death in poultry and the subsequent infection and death of over 140 humans. At present, there are only three licensed anti-Influenza drugs namely Relenza (Zanamivir - ZMV), Tamiflu (Oseltamivir - OTV) and Amantadine/ Rimantadine. The latter targets the M2 ion channel whereas the other compounds target neuraminidase (NA) and were designed through structure-based enzyme inhibitor programmes. Some structural knowledge of the Influenza neuraminidase is now known, due to remarkable advances in crystallographic techniques. The structure of H5N1 NA is particularly attractive because it offers new opportunities for drug design. Besides a profound impact that structural biology has had on understanding the Influenza virus and the rational design of antivirals, computational methods are now a viable partner to experiment in designing NA inhibitors. We herein discuss the development of current neuraminidase inhibitors, the emergence of resistance to them and recent research progress towards the development of new inhibitors. © 2010 Bentham Science Publishers Ltd.


Mitrasinovic P.M.,Belgrade Institute of Science and Technology
Journal of Chemical Information and Modeling | Year: 2015

The whole family of structurally distinct flavonoids has been recognized as a valuable source of prospective anticancer agents. There is experimental evidence demonstrating that some flavonoids, like flavopiridol (FLP) and quercetin (QUE), bind to DNA influencing their key physiological function. FLP is involved in the combined mode of interaction (intercalation and minor groove binding), while QUE is viewed as a minor groove binder. From a physical standpoint, experimental and theoretical studies have not so far provided a sufficiently consistent picture of the nature of interaction with DNA. Herein the sequence-dependent binding of FLP and of QUE (two representative examples of the structurally different flavonoids) with duplex DNA, containing a variety of the sequences of eight nucleotides (I: GGGGCCCC, II: GGCCGGCC, III: AAAATTTT, IV: AAGCGCTT, V: GCGCGCGC) in the 5-strand, is investigated using a sophisticated molecular dynamics (MD) approach. For various parts (helix, backbone, bases) of the DNA structure, the change of asymptotic (in terms of an infinite length of MD simulation) configurational entropy, being the thermodynamic consequence of DNA flexibility change due to ligand binding, is explored. As far as the sequence-dependent extent of DNA flexibility change upon QUE (or FLP) binding is concerned, for the entire double helix, increased flexibility is observed for I (or I ≈ II), while increased rigidity is found to be in the order of V > III > II > IV (or III > V > IV) for the rest of sequences. For the backbone, increased rigidity in the order of V > III > II > IV > I (or III > V > IV > I > II) is generally observed. For the nucleobases, increased flexibility is determined for I and II (I > II for both ligands), while increased rigidity in the order of V ≈ III > IV (or III > V > IV) is reported for the other sequences. Of the overall increased rigidity of the DNA structure upon ligand binding that is observed for the sequences III, IV, and V, about 50-70% comes from the sugar-phosphate backbone. Noteworthy is that the increased flexibility of the entire double helix and of the complete system of nucleobases upon ligand binding is only established for sequence I. The insights are further subtly substantiated by considering the configurational entropy contributions at the level of individual nucleobase pairs and of individual nucleo-base pair steps and by analyzing the sequence dependent estimates of intra-base pair entropy and inter-base pair entropy. The GGC triplet, which is part of the central tetramer (GGCC) of I, is concluded to be critical for binding of flavonoids, while the effect of the presence of ligand to the flexibility of nucleobases is localized through the intra-base pair motion of the intercalation site and its immediate vicinity. G-rich DNA sequences with consecutive Gs going before and/or after the critical GGC code (such as I: GGGGCCCC) are proposed to be uniquely specific for flavonoids. The configurational entropy contribution, as an upper bound of the true entropy contribution to the free energy in noncovalent binding, is demonstrated to influence the fundamental discrimination (intercalation vs groove binding) of DNA-flavonoid recognition modes. Some interesting implications for the structure-based design of optimal DNA binders are discussed. © 2015 American Chemical Society.


Mitrasinovic P.M.,Belgrade Institute of Science and Technology
Current Bioinformatics | Year: 2012

Amantadine is a specific anti-influenza a drug that inhibits viral replication by binding to the M2 channel and preventing proton conductance. The increasing resistance to amantadine in strains of the influenza A virus that infect both animals and humans has been highlighted frequently. Resistance is usually caused by one of several single mutations in the M2 channel, but variants with double mutations have also been reported. Attempts to develop alternative inhibitors of the M2 channel that are effective against the resistant mutants have been unsuccessful, mainly because of the lack of information on the precise mode of inhibitor binding. This review summarizes the advances made in determining the mechanisms of action of amantadine and the development of novel inhibitors of the M2 channel during the past 2 years. © 2012 Bentham Science Publishers.


Pavlov A.,Belgrade Institute of Science and Technology | Mitrasinovic P.M.,Belgrade Institute of Science and Technology
Current Organic Chemistry | Year: 2010

It has become apparent that molecular modeling is a powerful approach to examining the properties of biomolecular systems like nucleic acids and their noncovalent interactions with other substances. Theoretical studies dealing with the dynamics of such extended molecules are based on the molecular mechanics simulations exhibiting very low computational requirements without sacrificing accuracy. This advantage is balanced by a limitation that the electronic structure of the biomolecules is treated as being unaltered throughout the entire simulations. Hence, it is impossible to observe formation or break up of intra-and intermolecular interactions in order to describe the process of charge transfer. Consequently, it is indispensable to employ quantum-chemical methods, which would allow the change of electronic structure in a certain region of the biomolecular system under investigation. This article reviews advances over the last few years in which quantum-chemical wave function-based calculations have been applied to this problem. © 2010 Bentham Science Publishers Ltd.


Mitrasinovic P.M.,Belgrade Institute of Science and Technology
Current Bioinformatics | Year: 2012

Since most molecular studies on death of cells in tissues have been carried out on isolated cell populations due to known difficulties manifested by interactions with surrounding cells, a novel means of investigating general principles governing cellular functions under oxidative stress conditions is needed in order to shed more light on the background of cancer disease. It is believed that relevant signal transmission may be discovered by transition from molecular to modular cell biology. Systems-level kinetic models are thus expected to explain dynamic behavior and go far beyond the static pictures of the topologies of the signaling pathways. The outline of this review is to feature several representative problems, based on combined - experimental and systems biology studies over the last few years, with a particular emphasis both on the elucidation of how cells interpret the same signal stimulation in distinct fashions (cell death vs. cell survival) and on the identification of signaling molecules with therapeutic relevancy. The origin of oscillations in such molecular mechanisms under oxidative stress conditions and implications of these oscillatory non-linearities for the development of successful therapies are discussed. © 2012 Bentham Science Publishers.


Mitrasinovic P.M.,Belgrade Institute of Science and Technology
Current drug targets | Year: 2013

Epidermal growth factor receptors (EGFRs) belong to the ErbB family of receptor tyrosine kinases (TKs) involved in the proliferation of normal and malignant cells. As mutations and overexpression of ErbB TKs are implicated in carcinoma and glioblastoma and are related to both a very strong resistance to chemotherapy and a poor survival means that ErbB receptors are targets of considerable importance for anti-cancer drug design. Besides using monoclonal antibodies for anti-EGFR-related cancer therapeutics, small molecules - tyrosine kinase inhibitors are being considered as well. Some of these therapies have entered clinical trials or have been approved for clinical use. Based on experimental methods (radiometry, immunofluoroscence or luminescence, electrophoresis) that are mainly employed for measuring and interpreting the selectivity of protein kinase inhibitors, routine accomplishment of selectivity of small molecules for particular protein kinases is a substantial challenge. In light of this, we herein elaborate a computer-based protein engineering approach demonstrating its potential to be a viable supplement to experiment in modulating the affinity of ligand molecules for EGFR in an efficient manner. The structural basis of the remarkable strategy is also elucidated using our recent results obtained by means of molecular docking and molecular dynamics simulations. A few critical implications for successful structure-based design of prospective drug candidates against EGFR-related cancers are consequently discussed.


Mitrasinovic P.M.,Belgrade Institute of Science and Technology
Current Organic Chemistry | Year: 2010

In this article, theoretical and experimental advances in the understanding of electronic processes underlying organic/metal (O/M) interface energetics are reviewed and correlated. The critical outlook comprises several key standpoints: (1) electronic basis of barrier formation at organic/metal interfaces, (2) dependence of organic/metal interface energetics on molecular conformation, (3) organic/metal interfaces and charge injection in organic electronic devices, and (4) determination of the nature of O/M-bonded interactions using the electron density distribution. It is shown that, even in the case of weak interactions, the conformation of an organic molecule can be substantially changed upon adsorption on a metal surface, thus influencing the detailed understanding of organic/metal interfaces. Since interface energetics is essentially associated with a subtle balance amongst several mechanisms taking place at the metal-molecule contact and experiments usually detect only the cumulative effects of these mechanisms, experimental techniques and contemporary firstprinciple calculations are suggested to be combined in order to derive a comprehensive picture of the interfacial electronic structure. Because of the lack of satisfactory analytic theory for the elucidation of the dependence of charge injection on temperature, electric field, and energetic disorder in organic (opto-)electronic devices, some important experimental results are discussed. Our recently introduced general methodology for extrapolating the nature of interfacial interactions is herein elaborated by analyzing the topological features of the electron density at the organic/metal bond critical points determined by the quantum theory of atoms in molecules. The beauty is that the interfacial interactions are given physical definitions without invoking more traditional and non-invariant concepts, such as individual orbitals. © 2010 Bentham Science Publishers Ltd.

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