Tuesday, 26 April 2011

A novel web-oriented peptidomimetic compound virtual screening tool.

pepMMsMIMIC is a public, web-based virtual screening platform with the aim to suggest chemical compounds whose essential elements (pharmacophore) mimic a natural peptide or protein in 3D space which hopefully retain the ability to interact with the biological target and produce the typical biological effect.
Starting from the 3D structure of any protein-protein/peptide complex, pepMMsMIMIC design process begins by identifying the key residues that are responsible for the protein-protein recognition process. In this process, the peptide complexity is reduced and the basic pharmacophore model is defined by its critical structural features (peptide annotation points) in 3D space.
The pepMMsMIMIC paper has been accepted for publication in the NAR Web Server Issue 2011. I will post the Advance Access link in the near future.
Here the abstract:

pepMMsMIMIC is a novel web-oriented peptidomimetic compound virtual screening tool based on a multi-conformers 3D- similarity search strategy. Key to the development of pepMMsMIMIC has been the creation of a library of 17 million conformers calculated from 3.9 million commercially available chemicals collected in the MMsINC® database. Using as input the three-dimensional structure of a peptide bound to a protein, pepMMsMIMIC suggests which chemical structures are able to mimic the protein-protein recognition of this natural peptide using both pharmacophore and shape similarity techniques. We hope that the accessibility of pepMMsMIMIC will encourage medicinal chemists to de-peptidize protein-protein recognition processes of biological interest, thus increasing the potential of in silico peptidomimetic compound screening of known small molecules to expedite drug development.

Tuesday, 19 April 2011

MAISTAS: a tool for automatic structural evaluation of alternative splicing products

MAISTAS: a tool for automatic structural evaluation of alternative splicing products

Matteo Floris 1, Domenico Raimondo 2, Guido Leoni 2, Massimiliano Orsini 1, Paolo Marcatili 2 and Anna Tramontano 3,4*

Author Affiliations
1 CRS4-Bioinformatics Laboratory, c/o Sardegna Ricerche Scientific Park, Pula, 09010 Cagliari, Italy
2 Department of Biochemical Sciences, Sapienza University of Rome, P.le A. Moro, 5 - 00185 Rome, Italy 
Department of Physics, Sapienza University of Rome, P.le A. Moro, 5 - 00185 Rome, Italy.
4 Istituto Pasteur Fondazione Cenci Bolognetti, Sapienza University of Rome, P.le A. Moro, 5 - 00185 Rome, Italy.
*To whom correspondence should be addressed. Prof. Anna Tramontano, E-mail: anna.tramontano@uniroma1.it

Received October 26, 2010
Revision received March 17, 2011
Accepted March 22, 2011
Bioinformatics (2011) doi: 10.1093/bioinformatics/btr198 First published online: April 15, 2011  


Motivation: Analysis of the human genome revealed that the amount of transcribed sequence is an order of magnitude greater than the number of predicted and well characterized genes. A sizeable fraction of these transcripts is related to alternatively spliced forms of known protein coding genes. Inspection of the alternatively spliced transcripts identified in the pilot phase of the ENCODE project has clearly shown that often their structure might substantially differ from that of other isoforms of the same gene, and therefore that they might perform unrelated functions, or that they might even not correspond to a functional protein. Identifying these cases is obviously relevant for the functional assignment of gene products and for the interpretation of the effect of variations in the corresponding proteins. 

Results: Here we describe a publicly available tool that, given a gene or a protein, retrieves and analyses all its annotated isoforms, provides users with three-dimensional models of the isoform(s) of his/her interest whenever possible and automatically assesses whether homology derived structural models correspond to plausible structures. This information is clearly relevant. When the homology model of some isoforms of a gene does not seem structurally plausible, the implications are that either they assume a structure unrelated to that of the other isoforms of the same gene with presumably significant functional differences, or do not correspond to functional products. We provide indications that the second hypothesis is likely to be true for a substantial fraction of the cases. 

Wednesday, 13 April 2011

Splicing isoforms modeling, peptidomimetics and molecular dynamic made easy

This new season is started with 3 new accepted papers. Here a brief introduction, I will give more details very soon for each of them:

  1. MaƬstas (Bioinformatics, first name), a fully automatic pipeline aimed at building and assessing three-dimensional models for alternative splicing isoforms. The server builds, when possible, comparative structural models for all the splicing isoforms of a submitted gene or set of genes. The models are then analysed in terms of their suitability to exist in the monomeric state, i.e. when a warning appears in the model assessment, it cannot be excluded the possibility that other multimeric state may stabilize the structure. Moreover, the splicing isoform exonic coordinates are mapped on the final models.
  2. pep:MMs:MIMIC (Nucleic Acid Research, Web Server Issue, first name), a web-oriented tool that, given a peptide three-dimensional structure, is able to automate a multiconformers three-dimensional similarity search among 17 million of conformers calculated from 3.9 million of commercially available chemicals collected in the MMsINC database.
  3. ClickMD (Future Medicinal Chemistry), a web-based explicit solvent molecular dynamic simulator. ClickMD performs minimization, equilibration phase and a short run of classical MD. ClickMD works with PDB files of protein and peptides. You just needs a valid PDB file to start the MD simulation! You will receive an e-mail at the end of the simulation containing a link to a web page where you can download the MD results as: log files, trajectory files, energy and RMSD representations and graphs.