The efficiency of multi-target drugs: the network approach might help drug design

Despite considerable progress in genome- and proteome-based high-throughput screening methods and rational drug design, the number of successful single target drugs did not increase appreciably during the past decade. Network models suggest that partial inhibition of a surprisingly small number of targets can be more efficient than the complete inhibition of a single target. This and the success stories of multi-target drugs and combinatorial therapies led us to suggest that systematic drug design strategies should be directed against multiple targets. We propose that the final effect of partial, but multiple drug actions might often surpass that of complete drug action at a single target. The future success of this novel drug design paradigm will depend not only on a new generation of computer models to identify the correct multiple hits and their multi-fitting, low-affinity drug candidates but also on more efficient in vivo testing.Comment: 6 pages, 2 figures, 1 box, 38 reference

Correlation of intrinsic DNA curvature with DNA property periodicity

AbstractTwelve di- and trinucleotide parameter sets representing various structural, thermodynamic or bendability-related properties of DNA were tested in the prediction of DNA curvature applying Fourier analysis on curved and straight, A/T-type or G/C-type DNA sequence motifs. The best predictions were obtained with a new consensus bendability scale created by combining a nucleosome-based and a deoxyribonuclease I-based parameter set. Geometry calculations on the same sequences showed that the helical parameters derived from NMR structures can correctly predict curvature, as distinct from the parameters derived from X-ray crystallographic analysis

DPX: for the analysis of the protein core

Abstract Summary: In order to obtain an accurate description of the protein interior, we describe a simple and fast algorithm that measures the depth of each atom in a protein (dpx), defined as its distance (Å) from the closest solvent accessible atom. The program reads a PDB file containing the atomic solvent accessibility in the B-factor field, and writes a file in the same format, where the B-factor field now contains the dpx value. Output structure files can be thus directly displayed with molecular graphics programs like RASMOL, MOLMOL, Swiss-PDB View and colored according to dpx values. Availability: The algorithm is implemented in a standalone program written in C and its source is freely available at ftp.icgeb.trieste.it/pub/DPX or on request from the authors. Contact: [email protected]; [email protected]; [email protected] * To whom correspondence should be addressed

Szisztematikus kvantumkémiai számítások biomolekulák szerkezetének és energetikájának vizsgálatára = Systematic Quantum Chemical Calculations for Studying Structure and Energetics of Biomolecules

A DNS-bázisok tautomerizációja a mutációk egyik lehetséges mechanizmusa. A citozinra végzett kiterjedt elméleti dinamikai tanulmány atomi felbontású képet adott a tautomerizációról, amely a 'kanonikus' oxo-amino tautomerből a 'ritka' imino formába vezet. A komputeres szimulációkban a potenciálfelületet 'menet közben' ab initio kvantumkémiai (QC) számításból nyerjük, míg az atomok a klasszikus fizika szerint mozognak. A citozin maga nem mutat tautomerizációt (túl magas gát). A monohidratált komplexet tanulmányozva, mintegy 300, véletlenszerűen indított trajektóriából (egyenként 3000 lépés, 1 fs felbontás), egyetlen esetben észleltünk víz-közvetítette tautomerizációt. A mechanizmus egy összehangolt (concerted), szinkron folyamat, amelyet a részt vevő két hidrogén közti erős csatolás jellemez. Lazán kapcsolódik a projekthez egy benzimidazol-származék rezgési spektrumának elméleti számítása. E tanulmány a laboratóriumunkban korábban kifejlesztett Skálázott Kvantummechanikai (SQM) erőtér módszerét alkalmazta, és hasznos tapasztalatként szolgálhat nitrogén-heterociklusok - mint pl. a DNS-bázisok - jövőbeni számításaihoz. QC elméleti fejlesztésként, új eredményekről számoltunk be az MR-AQCC (Multireference Averaged Quadratic Coupled-Cluster) módszerrel kapcsolatban, ami különösen a gerjesztett eletronállapotokra tervezett vizsgálatainkhoz lehet fontos. | Tautomerization of DNA bases is one of the possible mechanisms of mutations. An extensive theoretical dynamics study on cytosine has given atomic-resolution details of the tautomerization which leads from the 'canonical' amino-oxo tautomer to the 'rare' imino-oxo form. In the computer simulations the potential surface is obtained 'on the fly' from ab initio quantum chemistry (QC), with the atoms moving classically. Cytosine itself shows no tautomerization (barrier too high). Studying the monohydrated complex, of about 300 randomly started trajectories (3000 steps each, 1 fs resolution) water-mediated tautomerization was observed in one single case. The mechanism is a concerted, synchronous process characterized by strong coupling between the two participating hydrogens. Theoretical calculation of the vibrational spectrum of a benzimidazol-derivative is loosely linked with the project. This study applied the method of Scaled Quantum Mechanical (SQM) force fields developed earlier in our laboratory and gives useful experience for future calculations on nitrogen heterocycles, like the DNA bases. As a theoretical development in QC, new results have been reported on the Multireference Averaged Quadratic Coupled-Cluster (MR-AQCC) method which may be important for future investigations on excited electronic states

Application of compression-based distance measures to protein sequence classification: a methodological study

Abstract Motivation: Distance measures built on the notion of text compression have been used for the comparison and classification of entire genomes and mitochondrial genomes. The present study was undertaken in order to explore their utility in the classification of protein sequences. Results: We constructed compression-based distance measures (CBMs) using the Lempel-Zlv and the PPMZ compression algorithms and compared their performance with that of the Smith–Waterman algorithm and BLAST, using nearest neighbour or support vector machine classification schemes. The datasets included a subset of the SCOP protein structure database to test distant protein similarities, a 3-phosphoglycerate-kinase sequences selected from archaean, bacterial and eukaryotic species as well as low and high-complexity sequence segments of the human proteome, CBMs values show a dependence on the length and the complexity of the sequences compared. In classification tasks CBMs performed especially well on distantly related proteins where the performance of a combined measure, constructed from a CBM and a BLAST score, approached or even slightly exceeded that of the Smith–Waterman algorithm and two hidden Markov model-based algorithms. Contact: [email protected] Supplementary information

Graph-representation of oxidative folding pathways

BACKGROUND: The process of oxidative folding combines the formation of native disulfide bond with conformational folding resulting in the native three-dimensional fold. Oxidative folding pathways can be described in terms of disulfide intermediate species (DIS) which can also be isolated and characterized. Each DIS corresponds to a family of folding states (conformations) that the given DIS can adopt in three dimensions. RESULTS: The oxidative folding space can be represented as a network of DIS states interconnected by disulfide interchange reactions that can either create/abolish or rearrange disulfide bridges. We propose a simple 3D representation wherein the states having the same number of disulfide bridges are placed on separate planes. In this representation, the shuffling transitions are within the planes, and the redox edges connect adjacent planes. In a number of experimentally studied cases (bovine pancreatic trypsin inhibitor, insulin-like growth factor and epidermal growth factor), the observed intermediates appear as part of contiguous oxidative folding pathways. CONCLUSIONS: Such networks can be used to visualize folding pathways in terms of the experimentally observed intermediates. A simple visualization template written for the Tulip package can be obtained from V.A