Quorum sensing is a bacterial mechanism that is essential in the pathogenesis of many infections, such as P. aeruginosa. These infections are strongly influenced by specific quorum sensing molecules, such as Autoinducer-2 (AI-2). AI-2 binds to quorum sensing receptors within bacteria leading to the up-regulation of virulence genes that cause biofilm formation and toxin production. Naturally-occurring brominated furanones isolated from the marine algae Delisea pulchra were previously found to possess properties which inhibited bacterial quorum sensing in AI-2 sensitive species.

The aim of this work was to create a series of novel halogenated furanones which can act as quorum sensing inhibitors of AI-2. Based on the lead from Delisea pulchra, a library of compounds was synthesised via the functionalisation of gem-dibromoolefin and gem-dichloroolefin intermediates using palladium-catalysed couplings, namely Suzuki and Sonogashira reactions. These compounds were subsequently evaluated for their effects on biofilm formation in selected microbes. Several molecules were confirmed to be highly effective biofilm inhibitors in multiple pathogens, including P. aeruginosa and C. albicans.

Molecular dynamics (MD) is a powerful tool used to study the evolution of molecular systems and predict their properties from the inherent interactions. GROMACS is a famous tool for MD and developed as open-source software. GROMACS is run from the command line with user-provided configuration files. However, the absence of a graphical user interface (GUI) of GROMACS and proper protocol to develop the input files (Ex: itp files, topology files, etc.) prevent the researcher from visualizing the MD trajectory in a real-time manner as well as addressing the structural problem. This issue was addressed by developing a graphical user interface of GROMACS as plugins for YASARA molecular graphics suite, called YAMACS. YAMACS is an open-source project and is available on GitHub (https://github.com/YAMACS-SML/YAMACS). The tool can perform MD simulations for protein, protein-ligand complex, membrane–protein complex, membrane-protein complex, and small molecule system. Easily YAMACS automatizes several steps of input file preparation and allows visualizing MD trajectory in real-time.

At this conference, I will present the application of YAMACS to simulate the complex sphingomyelin/POPC embedded in a membrane of POPC. I will also introduce a collaborative platform to create an open community of users and developers, extend the functionalities of YAMACS and improve the quality of computational drug design studies.

Drug discovery relies on computational medicinal chemistry for designing and identifying new drug-like chemicals, predicting properties and pharmacological activities of molecules, and optimizing lead structures. Focal Adhesion Kinase (FAK) is an emerging target for cancer chemotherapy with mounting evidence that FAK activation or elevated expression is associated with cancer progression, invasion, and drug resistance. This work envisages identification and in silico screening of potential FAK inhibitors which could further be evaluated. A total of 862 compounds were screened from the ZINC database and docked on the refined FAK enzyme using Autodock Vina. The best spotted hits were filtered for their druglikeness using SwissADME. These potential hits were further evaluated for their in silico toxicity using ProTox II software. Promiscuous hits identified by the docking score and applying Lipinski's Rule of five were ZINC43200601, ZINC95593660 and ZINC95595125. These hits showed high binding scores and passed the colander of in silico pharmacokinetic and toxicity proving these ligands propitious to be further evaluated. For selecting the Activity Spectra for Substances PASS program was used to screen the anticancer potential of the compound. The hits displayed antitumor profile.

The bacterial susceptibility and the translocation of fluoroquinolones (FQs) are influenced by pH, since it determines the proportion of microspecies of the drug. Norfloxacin (NOR) and Oxalic Acid (AO) are antibacterial compounds. In this work, we evaluated the antibacterial activity of the NOR-AO combination on the Escherichia coli ATCC 25922 strain using the checkerboard method. Besides, we analyzed the pH effect on the NOR-AO combination. We determined the extent of NOR ionization equilibrium and calculated the apparent log P to establish the lipophilicity of NOR at the different pHs assayed. The minimum inhibitory concentration (MIC) obtained for AO and NOR was 1250 µg/mL and 0.25 µg/mL, respectively. The interaction of NOR-AO was indifferent in the concentrations worked (CIF 1.12). However, an atypical behavior was observed in E.coli growth. We observed that at pH values ​​<5.8 and log D < -0.3, the cationic species of NOR predominates, decreasing its activity. As pH increases, the predominant species is zwitterionic with increased lipophilicity and restoration of NOR activity. Therefore, the acid conditions given by the presence of AO decrease the concentration of the neutral species of NOR and therefore the amount of drug capable of diffusing directly through the membrane. There is controversy in the literature regarding the mechanism of FQs translocation through the bacterial membrane, however, our results show that the pH of the medium is a determining factor that directly impacts the antibacterial activity. To deepen this study, we will continue testing new concentrations and combinations with other organic acids.

Medication non-adherence poses considerable challenges in managing chronic diseases and is associated with almost 200,000 deaths and €80-125 billion of potentially preventable direct (e.g. hospitalizations, waste of medication) and indirect (e.g. work productivity losses) costs in the European Union alone. The increasing awareness of the contribution of the acceptability of drug products by the patient to medication adherence and clinical outcomes is driving the integration of Patient Centric drug Product Design (PCDPD) into the pharmaceutical development process.

Regulatory agencies have addressed the relevancy of placing the patient in the center of pharmaceutical development. EMA has issued guideline/reflection papers for pediatric and older populations while FDA has developed a series of guidance documents on patient focused drug development with the primary goal to better incorporate the patient’s voice in drug development and evaluation.

PCDPD can be defined as the process of identifying the comprehensive needs of the target patient population to support the design of drug products. Three major factors are analyzed in PCDPD, namely patient, drug and drug product characteristics. This systematic approach integrates this insight which is translated to a Target Product Profile (TPP) to drive the pharmaceutical product design process.

Two case studies will be presented focused on the pediatric population and on patients with a chronic skin disorder (psoriasis) which will highlight the roadmap for a successful PCDPD.