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.

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.