Assemble-And-Match: A Novel Hybrid Tool for Enhancing Education and Research in Rational Structure Based Drug Design

Pouya Tavousi, Reza Amin, Sina Shahbazmohamadi
2018 Scientific Reports  
Rational drug design is the process of finding new medication that can activate or inhibit the biofunction of a target molecule by binding to it and forming a molecular complex. Here, shape and charge complementarities between drug and target are key. To help find effective drug molecules out of a huge pool of possibilities, physical and computer aided tools have been developed. Former offers a tangible experience of the molecular interactions yet lacks measurement and evaluation capabilities.
more » ... atter enables accurate and fast evaluations, but does not deliver the interactive tangible experience of physical models. We introduce a novel hybrid model called "Assemble-And-Match" where, we enhance and combine the unique features of the two categories. Assemble-And-Match works based on fabrication of customized molecular fragments using our developed software and a 3D printer. Fragments are hinged to each other in different combinations and form flexible peptide chains, conformable to tertiary structures, to fit in the binding pocket of a (3D printed) target molecule. Through embedded measurement marks, the molecular model is reconstructed in silico and its properties are evaluated. We expect Assemble-And-Match tool can enable combination of visuospatial perception with in silico computational power to aid research and education in drug design. Traditional drug discovery methods have a basis in trial-and-error 1 . In contrary, rational drug design approaches attempt to modulate a specific biological target in hope for a therapeutic value 2 . Typically, the ligand drug molecule must be designed such that it can attach to the binding site of the target strongly (i.e. with high affinity) and sometimes uniquely (i.e. with high specificity). This happens if there is a complimentary relationship between the drug and the target in shape (for affinity) and in charge (for specificity) 3 . Finding the best drug molecule candidate among a large library of possible ligands requires a way to evaluate the individual items 4,5 . Due to cost and time limitations, experimental screening of all possibilities is ruled out 6 . Therefore, several tools are employed to help narrow down the primary set of candidates. These tools that, are used both in research labs for conducting more efficient research studies and in the educational environments to raise the students' comprehension of molecular structures and interactions, can be classified into two categories of physical 7,8 and computer aided molecular models 9 . Computational tools attempt to rank a set of either collected or enumerated candidates based on a scoring function 10 . The scoring function which is supposed to reflect the binding affinity between the drug and target molecules, is commonly derived semi-empirically 11 but can also be obtained from density functional theory 12 or ab-initio quantum chemistry techniques 13 . Scoring function can also be the result of knowledge based methods, where statistical and data mining tools are used for pattern extraction and data fitting from experimental binding affinity examples 14 . In a perfect world, the drug design screening tool will result in only one candidate solution. So, in turn, chemical synthesis of only one molecule will be sufficient. However in reality, because of the imperfection of the models, even after several iterations of computational evaluations, still several candidates must be chemically synthesized to compare their properties through experimental assays 15 . Published: xx xx xxxx OPEN www.nature.com/scientificreports/ 2 SciEntific REPORTS | (2018) 8:849 |
doi:10.1038/s41598-017-18151-x pmid:29339792 pmcid:PMC5770410 fatcat:f6petpolcvdcpebgvt42ys7vwu