An effective HIV-1 integrase inhibitor screening platform: Rationality validation of drug screening,conformational mobility and molecular recognition analysis for PFV integrase complex with viral DNA

As an important target for the development of novel anti-AIDS drugs, HIV-1 integrase (IN) has been widely concerned. However, the lack of a complete accurate crystal structure of HIV-1 IN greatly blocks the discovery of novel inhibitors. In this work, an effective HIV-1 IN inhibitor screening platform, namely PFV IN, was filtered from all species of INs. Next, the 40.8% similarity with HIV-1 IN, as well as the high efficiency of virtual screening and the good agreement between calculated binding free energies and experimental ones all proved PFV IN is a promising screening platform for HIV-1 IN inhibitors. Then, the molecular recognition mechanism of PFV IN by its substrate viral DNA and six naphthyridine derivatives (NRDs) inhibitors was investigated through molecular docking, molecular dynamics simulations and water-mediated interactions analyses. The functional partition of NRDs IN inhibitors could be divided into hydrophobic and hydrophilic ones, and the Mg²⁺ ions, water molecules and conserved DDE motif residues all interacted with the hydrophilic partition, while the bases in viral DNA and residues like Tyr212, Pro214 interacted with the hydrophobic one. Finally, the free energy landscape (FEL) and cluster analyses were performed to explore the molecular motion of PFV IN-DNA system. It is found that the association with NRDs inhibitors would obviously decrease the motion amplitude of PFV IN-DNA, which may be one of the most potential mechanisms of IN inhibitors. This work will provide a theoretical basis for the inhibitor design based on the structure of HIV-1 IN.     

On the use of software design models in software development practice: An empirical investigation

Research into software design models in general, and into the UML in particular, focuses on answering the question how design models are used, completely ignoring the question if they are used. There is an assumption in the literature that the UML is the de facto standard, and that use of design models has had a profound and substantial effect on how software is designed by virtue of models giving the ability to do model-checking, code generation, or automated test generation. However for this assumption to be true, there has to be significant use of design models in practice by developers.This paper presents the results of a survey summarizing the answers of 3785 developers answering the simple question on the extent to which design models are used before coding. We relate their use of models with (i) total years of programming experience, (ii) open or closed development, (iii) educational level, (iv) programming language used, and (v) development type.The answer to our question was that design models are not used very extensively in industry, and where they are used, the use is informal and without tool support, and the notation is often not UML. The use of models decreased with an increase in experience and increased with higher level of qualification. Overall we found that models are used primarily as a communication and collaboration mechanism where there is a need to solve problems and/or get a joint understanding of the overall design in a group. We also conclude that models are seldom updated after initially created and are usually drawn on a whiteboard or on paper.