Pathfinder-Driven Chemical Space Exploration and Multiparameter Optimization in Tandem with Glide/IFD and QSAR-Based Active Learning Approach to Prioritize Design Ideas for FEP+ Calculations of SARS-CoV-2 PLpro Inhibitors.

A global pandemic caused by the SARS-CoV-2 virus that started in 2020 and has wreaked havoc on humanity still ravages up until now. As a result, the negative impact of travel restrictions and lockdowns has underscored the importance of our preparedness for future pandemics. The main thrust of this work was based on addressing this need by traversing chemical space to design inhibitors that target the SARS-CoV-2 papain-like protease (PLpro). Pathfinder-based retrosynthesis analysis was used to generate analogs of GRL-0617 using commercially available building blocks by replacing the naphthalene moiety. A total of 10 models were built using active learning QSAR, which achieved good statistical results such as an R2 > 0.70, Q2 > 0.64, STD Dev < 0.30, and RMSE < 0.31, on average for all models. A total of 35 ideas were further prioritized for FEP+ calculations. The FEP+ results revealed that compound 45 was the most active compound in this series with a ΔG of −7.28 ± 0.96 kcal/mol. Compound 5 exhibited a ΔG of −6.78 ± 1.30 kcal/mol. The inactive compounds in this series were compound 91 and compound 23 with a ΔG of −5.74 ± 1.06 and −3.11 ± 1.45 kcal/mol. The combined strategy employed here is envisaged to be of great utility in multiparameter lead optimization efforts, to traverse chemical space, maintaining and/or improving the potency as well as the property space of synthetically aware design ideas.

Pharmacophore Model-Based Virtual Screening Workflow for Discovery of Inhibitors Targeting Plasmodium falciparum Hsp90.

Plasmodium falciparum causes the most lethal and widespread form of malaria. Eradication of malaria remains a priority due to the increasing number of cases of drug resistance. The heat shock protein 90 of P. falciparum (PfHsp90) is a validated drug target essential for parasite survival. Most PfHsp90 inhibitors bind at the ATP binding pocket found in its N-terminal domain, abolishing the chaperone's activities, which leads to parasite death. The challenge is that the NTD of PfHsp90 is highly conserved, and its disruption requires selective inhibitors that can act without causing off-target human Hsp90 activities. We endeavored to discover selective inhibitors of PfHsp90 using pharmacophore modeling, virtual screening protocols, induced fit docking (IFD), and cell-based and biochemical assays. The pharmacophore model (DHHRR), composed of one hydrogen bond donor, two hydrophobic groups, and two aromatic rings, was used to mine commercial databases for initial hits, which were rescored to 20 potential hits using IFD. Eight of these compounds displayed moderate to high activity toward P. falciparum NF54 (i.e., IC50s ranging from 6.0 to 0.14 µM) and averaged >10 in terms of selectivity indices toward CHO and HepG2 cells. Additionally, four compounds inhibited PfHsp90 with greater selectivity than a known inhibitor, harmine, and bound to PfHsp90 with weak to moderate affinity. Our findings support the use of a pharmacophore model to discover diverse chemical scaffolds such as FM2, FM6, F10, and F11 exhibiting anti-Plasmodium activities and serving as valuable new PfHsp90 inhibitors. Optimization of these hits may enable their development into potent leads for future antimalarial drugs.

Electrocatalysis of Endosulfan Based on Fe3O4: An Experimental and Computational Approach.

The present work reports the electrocatalytic oxidation of the organochlorine pesticide endosulfan (EDS) using iron oxide (Fe3O4) nanoparticles synthesized from Callistemon viminalis leaf extracts. As a sensor for EDS, Fe3O4 was combined with functionalized multiwalled carbon nanotubes (f-MWCNTs) on a glassy carbon electrode (GCE). Cyclic voltammetry, electrochemical impedance spectroscopy, and the differential pulse voltammetry experiment were conducted to investigate the electrochemistry of EDS on the GCE/f-MWCNT/Fe3O4 sensor. Based on optimized experimental conditions, the reports of analytical parameters show a limit of detection of 3.3 µM and an effective sensitivity of 0.06464 µA/µM over a range of concentrations from 0.1 to 20 µM. With the proposed method, we were able to demonstrate recoveries between 94 and 110% for EDS determinations in vegetables. Further, a series of computational modeling studies were carried out to better understand the EDS surface adsorption phenomenon on the GCE/f-MWCNT/Fe3O4 sensor. The highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy gap (-5.18 eV) computed by density functional theory (DFT) supports the layer-by-layer electrode modification strategy's charge transfer and stability. Finally, transition state modeling was able to predict and confirm the mechanism of endosulfan oxidation.

Toward a quality guide to facilitate the transference of analytical methods from research to testing laboratories: a case study.

At present, there is no single viewpoint that defines QA strategies in analytical chemistry. On the other hand, there are no unique protocols defining a set of analytical tasks and decision criteria to be performed during the method development phase (e.g., by a single research laboratory) in order to facilitate the transference to the testing laboratories intending to adapt, validate, and routinely use this method. This study proposes general criteria, a priori valid for any developed method, recommended as a provisional quality guide containing the minimum internal tasks necessary to publish new analytical method results. As an application, the selection of some basic internal quality tasks and the corresponding accepted criteria are adapted to a concrete case study: indirect differential pulse polarographic determination of nitrate in water samples according to European Commission requisites. Extra tasks to be performed by testing laboratories are also outlined.