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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. Source


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. Source


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. Source


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

Epidermal growth factor receptors belong to the ErbB family of receptor tyrosine kinases (TKs) involved in the proliferation of normal and malignant cells. EGFR has attracted considerable attention as a target for cancer therapy. The findings reported herein are believed to provide some novel insights into the design of effective drugs for the therapeutic treatment of EGFR-related cancers. In particular, it is shown using sophisticated computational tools in a systematic way that the affinity of a wide spectrum of thiazolo[4,5-d] pyrimidine analogs can be carefully tuned up by seeking the desired goal in the structural modifications of EGFR, such as single point mutations of the critical EGFR residues in the active site. It is also demonstrated that a large number of the small ligand molecules can be efficiently divided into subgroups of the structurally similar ligands and that every such a subgroup has its unique inhibitory activity signature. The protein engineering approach, as quite reproducible, is proposed to be a viable partner to experiment in addressing a variety of issues, including investigation of clinically important mutations, development of drug resistance, identification of the most promising anti-cancer drug candidates, etc. © 2014 Bentham Science Publishers. Source


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. Source

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