Luteolin: a blocker of SARS-CoV-2 cell entry based on relaxed complex scheme, molecular dynamics simulation, and metadynamics.

Natural products have served human life as medications for centuries. During the outbreak of COVID-19, a number of naturally derived compounds and extracts have been tested or used as potential remedies against COVID-19. Tetradenia riparia extract is one of the plant extracts that have been deployed and claimed to manage and control COVID-19 by some communities in Tanzania and other African countries. The active compounds isolated from T. riparia are known to possess various biological properties including antimalarial and antiviral. However, the underlying mechanism of the active compounds against SARS-CoV-2 remains unknown. Results in the present work have been interpreted from the view point of computational methods including molecular dynamics, free energy methods, and metadynamics to establish the related mechanism of action. Among the constituents of T. riparia studied, luteolin inhibited viral cell entry and was thermodynamically stable. The title compound exhibit residence time and unbinding kinetics of 68.86 ms and 0.014 /ms, respectively. The findings suggest that luteolin could be potent blocker of SARS-CoV-2 cell entry. The study shades lights towards identification of bioactive constituents from T. riparia against COVID-19, and thus bioassay can be carried out to further validate such observations.

Accommodating receptor flexibility and free energy calculation to reduce false positive binders in the discovery of natural products blockers of SARS-COV-2 spike RBD-ACE2 interface.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), which causes coronavirus disease-19 (COVID-19) has caused more than 2 million deaths around the globe. The high transmissibility rate of the disease is related to the strong interaction between the virus spike receptor-binding domain (RBD) and the human angiotensin-converting enzyme 2 (ACE2) as documented in several reports. In this study, using state-of-the-art computational methods, natural products were screened and their molecular mechanism to disrupt spike RBD-ACE2 recognition was evaluated. There is the sensitivity of results to receptor ensemble docking calculations. Binding free energy and MD simulation are important tools to evaluate the thermodynamics of binding stability and the capacity of top hits to disrupt RBD-ACE2 recognition. The free energy profiles provide a slight decrease in binding affinity of the virus-receptor interaction. Three flavonoids parvisoflavone B (3), alpinumisoflavone (5) and norisojamicin (2) were effective in blocking the viral entry by binding strongly at the spike RBD-ACE2 interface with the inhibition constant of 0.56, 0.78 and 0.93 µM, respectively. The same compounds demonstrated similar effect on free ACE2 protein. Compound (2), also demonstrated ability to bind strongly on free spike RBD. Well-tempered metadynamics established that parvisoflavone B (3) works by binding to three sites namely interface α, ß and loop thereby inhibiting viral cell entry. Owing to their desirable pharmacokinetic properties, the presented top hit natural products are suggested for further SARS-COV-2 molecular targets and subsequent in vitro and in vivo evaluations.

In silico study of the inhibition of SARS-COV-2 viral cell entry by neem tree extracts.

The outbreak of COVID-19, caused by SARS-COV-2, is responsible for higher mortality and morbidity rates across the globe. Until now, there is no specific treatment of the disease and hospitalized patients are treated according to the symptoms they develop. Efforts to identify drugs and/or vaccines are ongoing processes. Natural products have shown great promise in the treatment of many viral related diseases. In this work, using in silico methods, bioactive compounds from the neem tree were investigated for their ability to block viral cell entry as spike RBD-ACE2 inhibitors. Azadirachtin H, quentin and margocin were identified as potential compounds that demonstrated viral cell entry inhibition properties. The structural re-orientation of azadirachtin H was observed as the mechanism for viral cell entry inhibition. These compounds possessed good pharmacodynamic properties. The proposed molecules can serve as a starting point towards developing effective anti-SARS-COV-2 drugs targeting the inhibition of viral cell entry upon further in vitro and in vivo validation.

Cation-π interactions drive hydrophobic self-assembly and aggregation of niclosamide in water.

The beneficial medicinal effects of niclosamide have been reported to be hampered by poor aqueous solubility and so a higher concentration dosage is required. In this work, we have studied the aggregation properties of niclosamide in water by varying the number of monomers. We have employed all-atom classical molecular dynamics simulation in order to explore such properties. The equilibrium structure exists in an aggregated state with structural rearrangements of the stacking units. Niclosamide monomers tend to form clusters in an orderly manner and tend to aggregate in parallel and antiparallel orientations of the phenyl rings as the monomers are increased in number from 4 to 9. Upon increasing the size from 9 to 14, and from 49 to 150, a considerable dominance of the metastable parallel arrangement is observed, resulting in the formation of a closely packed cluster with hydrophobic contacts. The metastable conformation self-arranges to a T-shape before forming a stable planar antiparallel displaced conformation. The aggregated π-π parallel and cation-π antiparallel clusters in water exist in a ß-conformer. We further observed that formation of a stable cluster aggregate entails the formation of an intermediate metastable cluster that disperses in solution forming a large stable cluster. We also discovered that movement of the water is faster in less aggregated clusters and as the cluster size increases, the mobility rate becomes much slower.

A review of the newly identified impurity profiles in methamphetamine seizures.

Forensic intelligence of synthetic illicit drugs suffers a problem of continuous introduction of new synthetic methods, modification of the existing routes of manufacture, and adulterations practiced by criminal networks. Impurity profiling has been indispensable in methamphetamine intelligence based on precursors, synthetic routes, and chemical modifications during trafficking. Law enforcement authorities maintain the credibility and integrity of intelligence information through constant monitoring of the chemical signatures in the illicit drug market. Changes in the synthetic pattern result in new impurity profiles that are important in keeping valuable intelligence information on clandestine laboratories, new synthetic routes, trafficking patterns, and geographical sources of illicit Methamphetamine. This review presents a critical analysis of the methamphetamine impurity profiles and more specifically, profiling based on impurity profiles from Leuckart, Reductive amination, Moscow, Emde, Nagai, Birch, Moscow route; a recent nitrostyrene route and stable isotope signatures. It also highlights the discrimination of ephedrine from pseudoephedrine sources and the emerging methamphetamine profiling based on stable isotopes.