Veljko Veljkovic

Is it Possible to Analyze DNA and Protein Sequences by the Methods of Digital Signal Processing

Informational content of linear macromolecules (DNA, RNA, and proteins) is analyzed by the method of digital signal processing. Each element (amino acid or nucleotide) of macromolecules is represented by the corresponding value of electron-ion interaction potential. This numerical representation of the primary structure of macromolecules is subjected to digital signal processing in order to extract the information corresponding to biological function. It is shown that the multiple cross spectrum of functionally related sequences exhibits significant peak frequencies. In the case of functionally unrelated sequences such peaks were not found. Peak frequencies are different for different biological functions. Based on this, we conjecture that the peak frequencies in the multiple cross spectrum of sequences with the same boilogical function are related to this biological function.

Characterization of conserved properties of hemagglutinin of H5N1 and human influenza viruses: possible consequences for therapy and infection control

BackgroundEpidemics caused by highly pathogenic avian influenza virus (HPAIV) are a continuing threat to human health and to the worlds economy. The development of approaches, which help to understand the significance of structural changes resulting from the alarming mutational propensity for human-to-human transmission of HPAIV, is of particularly interest. Here we compare informational and structural properties of the hemagglutinin (HA) of H5N1 virus and human influenza virus subtypes, which are important for the receptor/virus interaction.ResultsPresented results revealed that HA proteins encode highly conserved information that differ between influenza virus subtypes H5N1, H1N1, H3N2, H7N7 and defined an HA domain which may modulate interaction with receptor. We also found that about one third of H5N1 viruses which are isolated during the 2006/07 influenza outbreak in Egypt possibly evolve towards receptor usage similar to that of seasonal H1N1.ConclusionThe presented results may help to better understand the interaction of influenza virus with its receptor(s) and to identify new therapeutic targets for drug development.

Application Of The EIIP/ISM Bioinformatics Concept in Development of New Drugs

The development of a new therapeutic drug is a complex, lengthy and expensive process. On average, only one out of 10,000 - 30,000 originally synthesized compounds will clear all the hurdles on the way to becoming a commercially available drug. The process of early and full preclinical discovery and clinical development for a new drug can take twelve to fifteen years to complete, and cost approximately 800 million dollars. The field of bioinformatics has become a major part of the drug discovery pipeline playing a key role in improvement and acceleration of this time and money consuming process. Here we reviewed the application of the EIIP/ISM bioinformatics concept for the development of new drugs. This approach, connecting the electron-ion interaction potential of organic molecules and their biological properties, can significantly reduce development time through (i) identification of promising lead compounds that have some activity against a disease by fast virtual screening of the large molecular libraries, (ii) refinement of selected lead compounds in order to increase their biological activity, and (iii) identification of domains of proteins and nucleotide sequences representing potential targets for therapy. Special attention is paid in this review to the application of the EIIP/ISM bioinformatics platform along with other experimental techniques (screening of a phage displayed peptide libraries, testing selected peptides and small molecules for antiviral activity in vitro) in development of HIV entry inhibitors, representing a new generation of the AIDS drugs.

AIDS epidemic at the beginning of the third millennium: time for a new AIDS vaccine strategy.

Current expansion of AIDS pandemic significantly accelerates AIDS vaccine research resulting in development and clinical testing of several AIDS vaccine candidates. At the same time, available experimental and clinical data demonstrate that current AIDS vaccine strategy is unsuccessful resulting in development of inefficient and harmful vaccines. This overview briefly summarizes reported results which point out the requirement for moratorium on the current clinical trials of HIV-1 gp120/160 vaccines and urgent need for development of a new, efficient and safe AIDS vaccine strategy.

Spectral and sequence similarity between vasoactive intestinal peptide and the second conserved region of human immunodeficiency virus type 1 envelope glycoprotein (gp120): Possible consequences on prevention and therapy of aids

Recently, in sera of HIV infected individuals, antibodies recognizing nonimmunogenic C-terminal domain of the second conserved region of HIV-1 gp120 were identified (1). These antibodies are significantly more prevalent in asymptomatic carriers than in AIDS patients (1). Here we reported striking spectral and sequence homologies between human vasoactive intestinal peptide (VIP) and the conserved peptide derived from HIV-1 gp120 which binds these antibodies. The possible consequences of these findings on therapy and prevention of AIDS are discussed.

Discovery of New Therapeutic Targets by the Informational Spectrum Method

The field of bioinformatics has become a major part of the drug discovery pipeline playing a key role in improvement and acceleration of this time and money consuming process. Here we review the application of the informational spectrum method (ISM), a virtual spectroscopy method for structure/function analysis of proteins, in identification of functional protein domains representing candidate therapeutic targets for drugs against human immunodeficiency virus (HIV)-1, anthrax, highly pathogenic influenza virus H5N1 and cardiovascular diseases.

Computational studies of the interaction between the HIV-1 integrase tetramer and the cofactor LEDGF/p75: insights from molecular dynamics simulations and the informational spectrum method.

A crystal structure of the integrase binding domain (IBD) of the lens epithelium‐derived growth factor (LEDGF/p75) in complex with the dimer of the HIV‐1 integrase (IN) catalytic core domain (CCD) provides useful information that might help in the understanding of essential protein‐protein contacts in HIV‐1. However, mutagenic studies indicated that interactions between the full‐length proteins were more extensive than the contacts observed in the co‐crystal structure of the isolated domains. On the other hand, the biochemical characterization of the interaction between full‐length IN and LEDGF/p75 has recently proved that LEDGF/p75 promotes IN tetramerization with two LEDGF/p75 IBD molecules bound to the IN tetramer. This experimental evidence suggests that to obtain a complete structural description of the interactions between the two proteins, the full‐length tetrameric structure of IN should be considered. Our aim was to obtain a detailed picture of HIV‐1 IN interactions with cellular co‐factors that was of general interest, particularly for the development of small molecule IN inhibitors, which mimic the IBD of LEDGF/p75. To this end, we performed bioinformatics analyses to identify protein sequence domains involved in long‐range recognition. Subsequently, we applied molecular dynamics techniques to investigate the detailed interactions between the complete tetrameric form of IN and two molecules of the IBD of LEDGF/p75. Our dynamic picture is in agreement with experimental data and, thereby, provides new details of the IN‐LEDGF/p75 interaction. Proteins 2010.

Protein and DNA-sequence homologies between the V3-loop of human immunodeficiency virus type I envelope protein gp120 and immunoglobulin variable regions

We found that a common amino acid sequence motif exists between the V3-loop region of the human immunodeficiency virus type I envelope protein HIV gp120 and the human immunoglobulin heavy chain variable regions of subclass III (Ig VH-III). In the Ig VH-III sequences, the common motif overlaps with framework-1, complementarity-determining-region-1 and framework-2. In the homologous regions, the two groups of sequences also have a similar distribution of residue variability. On the DNA sequence level, the homology includes the conserved rearrangement signals of the VH-III genes, which lends support to the speculation that the V3 region of gp120 also may be involved in rearrangement processes.

Virtual screen for repurposing approved and experimental drugs for candidate inhibitors of EBOLA virus infection

The ongoing Ebola virus epidemic has presented numerous challenges with respect to control and treatment because there are no approved drugs or vaccines for the Ebola virus disease (EVD). Herein is proposed simple theoretical criterion for fast virtual screening of molecular libraries for candidate inhibitors of Ebola virus infection. We performed a repurposing screen of 6438 drugs from DrugBank using this criterion and selected 267 approved and 382 experimental drugs as candidates for treatment of EVD including 15 anti-malarial drugs and 32 antibiotics. An open source Web server allowing screening of molecular libraries for candidate drugs for treatment of EVD was also established.

Sequence similarity between human immunodeficiency virus type 1 envelope protein (gp120) and human proteins: a new hypothesis on protective antibody production.

The production of neutralizing antibodies against the central portion of HIV-1 gp120 requires cooperation between T cell and B cell epitopes of this region. We found a motif common to the carboxyterminus of the second conserved region of HIV-1 gp120 and sequences of some human proteins, most of which participate in immune response. The sequence of gp120 of HTLV-IIIB with the highest T-cell reactivity incorporates this motif. It is suggested that the existence of this sequence motif in the central region of the HIV-1 gp120 molecule prevents the production of neutralizing antibodies against the virus in humans.