DescriptionTo predict and determine as accurately as possible the 3-dimensional (3D) structure of proteins of interest is of great importance in numerous R&D fields within the Life Sciences sector. For the pharmaceutical industry for instance that approach can deliver very useful information for the design and optimization of many drugs. In the paper and chemical industry one can investigate amino-acid point mutations to adapt the efficacy of industrial enzyme to non-native temperature and pH conditions to accommodate to specific production processes. 3D protein structure can be assessed using in-silico and / or X-ray crystallography approaches. BioXpr has been focusing on the in-silico approach by homology which consists in comparing virtually closely related structures determined by X-ray crystallography to predict the structure of the protein of interest. To that end BioXpr’s scientists developed a dedicated software called ESyPred3D. The software has achieved top rankings in international CASP4, CAFASP3 and EVA contests. Our methods takes advantage from the increased alignment performances of a new alignment strategy using neural networks. Alignments are obtained by combining, weighting and screening the results of several multiple alignment programs to provide high-throughput generation of high-quality protein models. Our experise in that field can be used for the following applications (non-exhaustive list):·Protein modeling, ·Small molecules docking, ·Mass spectrometry data analysis ·Structure-based drug design,·Protein engineering, ·Mutation and stability studies, …Case studyChallenge :BioXpr has been contracted by a biotech company leader in the field of bone marrow research. The project consisted in the in-silico 3D modelisation of the external part of a dimeric trans-membrane receptor protein, the in-silico 3D modelisation of dimeric ligand therapeutics candidates and the in-silico docking and screening of the dimeric ligand candidatesinto the receptor to identify the best drug candidate.Analyis and Actions:BioXpr successfully achieved the following steps:•Modelling by homology with a tightly-related monomer protein of the external part of the dimeric trans-membrane receptor protein•Modeling of the two small dimeric therapeutic ligand drug candidates•After careful evaluation it turned out that automatic docking of the ligand candidates into the receptor was simply not possible in that instance. Consequently BioXpr carried out manual docking by superimposition on a reference ligand using molecular mechanics to freeze common parts.•The docking work was quality checked by several methods including semi-empirical quantum mechanicsResults and perspectivesBioXpr managed to rank the two candidates in terms of affinity for the receptor and stability of the binding. Discussions are in progress to move on with the work to fine-tune the understanding of the binding between the best ligand candidate and thereceptor.(link to a PDF detailing the Case Study)
