Modeling studies on the role of vitamins B1 (thiamin), B3 (nicotinamide), B6 (pyridoxamine), and caffeine as potential leads for the drug design against COVID-19.

In response to the COVID-19 pandemic, and the lack of effective and safe antivirals against it, we adopted a new approach in which food supplements with vital antiviral characteristics, low toxicity, and fast excretion have been targeted. The structures and chemical properties of the food supplements were compared to the promising antivirals against SARS-COV-2. Our goal was to exploit the food supplements to mimic the topical antivirals' functions but circumventing their severe side effects, which has limited the necessary dosage needed to exhibit the desired antiviral activity. On this line, after a comparative structural analysis of the chemicals mentioned above, and investigation of their potential mechanisms of action, we selected caffeine and some compounds of the vitamin B family and further applied molecular modeling techniques to evaluate their interactions with the RDB domain of the Spike protein of SARS-CoV-2 (SC2Spike) and its corresponding binding site on human ACE-2 (HssACE2). Our results pointed to vitamins B1 and B6 in the neutral form as potential binders to the HssACE2 RDB binding pocket that might be able to impair the SARS-CoV-2 mechanism of cell invasion, qualifying as potential leads for experimental investigation against COVID-19.

Fragment-Based Phenotypic Lead Discovery To Identify New Drug Seeds That Target Infectious Diseases.

Fragment-based lead discovery has emerged over the last decades as one of the most powerful techniques for identifying starting chemical matter to target specific proteins or nucleic acids in vitro. However, the use of such low-molecular-weight fragment molecules in cell-based phenotypic assays has been historically avoided because of concerns that bioassays would be insufficiently sensitive to detect the limited potency expected for such small molecules and that the high concentrations required would likely implicate undesirable artifacts. Herein, we applied phenotype cell-based screens using a curated fragment library to identify inhibitors against a range of pathogens including Leishmania, Plasmodium falciparum, Neisseria, Mycobacterium, and flaviviruses. This proof-of-concept shows that fragment-based phenotypic lead discovery (FPLD) can serve as a promising complementary approach for tackling infectious diseases and other drug-discovery programs.

Reactivation of VX-Inhibited Human Acetylcholinesterase by Deprotonated Pralidoxime. A Complementary Quantum Mechanical Study.

In the present work, we performed a complementary quantum mechanical (QM) study to describe the mechanism by which deprotonated pralidoxime (2-PAM) could reactivate human (Homo sapiens sapiens) acetylcholinesterase (HssAChE) inhibited by the nerve agent VX. Such a reaction is proposed to occur in subsequent addition-elimination steps, starting with a nucleophile bimolecular substitution (SN2) mechanism through the formation of a trigonal bipyramidal transition state (TS). A near attack conformation (NAC), obtained in a former study using molecular mechanics (MM) calculations, was taken as a starting point for this project, where we described the possible formation of the TS. Together, this combined QM/MM study on AChE reactivation shows the feasibility of the reactivation occurring via attack of the deprotonated form of 2-PAM against the Ser203-VX adduct of HssAChE.

Revealing atropisomer axial chirality in drug discovery.

An often overlooked source of chirality is atropisomerism, which results from slow rotation along a bond axis due to steric hindrance and/or electronic factors. If undetected or not managed properly, this time-dependent chirality has the potential to lead to serious consequences, because atropisomers can be present as distinct enantiomers or diastereoisomers with their attendant different properties. Herein we introduce a strategy to reveal and classify compounds that have atropisomeric chirality. Energy barriers to axial rotation were calculated using quantum mechanics, from which predicted high barriers could be experimentally validated. A calculated rotational energy barrier of 20 kcal mol(-1) was established as a suitable threshold to distinguish between atropisomers and non-atropisomers with a prediction accuracy of 86%. This methodology was applied to subsets of drug databases in the course of which atropisomeric drugs were identified. In addition, some drugs were exposed that were not yet known to have this chiral attribute. The most valuable utility of this tool will be to predict atropisomerism along the drug discovery pathway. When used in concert with our compound classification scheme, decisions can be made during early discovery stages such as "hit-to-lead" and "lead optimization," to foresee and validate the presence of atropisomers and to exercise options of removing, further stabilizing, or rendering the chiral axis of interest more freely rotatable via SAR design, thereby decreasing this potential liability within a compound series. The strategy can also improve drug development plans, such as determining whether a drug or series should be developed as a racemic mixture or as an isolated single compound. Moreover, the work described herein can be extended to other chemical fields that require the assessment of potential chiral axes.