Structure based design, stability study and synthesis of the dinitrophenylhydrazone derivative of the oxidation product of lanosterol as a potential P. falciparum transketolase inhibitor and in-vivo antimalarial study.

The growing resistance to the current antimalarial drugs in the absence of a vaccine can be effectively tackled by identifying new metabolic pathways that are essential to the survival of the malaria parasite and developing new drugs against them. Triterpenes and steroids are the most abundant group of natural products with a great variety of biological activities. However, lanosterol is not known to possess any significant biological activity. In this study the binding and interactions of a dinitrophenyl hydrazine (DNP) derivative of lanosterol, LAN (a derivative that incorporates a substantially polar moiety into the steroid) with P. falciparum transketolase was studied by molecular docking and MD simulation with the view to exploit the DNP derivative as a lead in antimalarial chemotherapy development considering that the P. falciparum transketolase (PfTk) is a novel target in antimalarial chemotherapy. The enzyme catalyses the production of ribose sugars needed for nucleic acid synthesis; it lacks a three-dimensional (3D) structure necessary for docking because it is difficult to obtain a crystalline form. A homology model of PfTk was constructed using Saccharomyces cerevisiae transketolase (protein data bank ID of 1TRK) as the template. The compound was observed to have Free Energy of Binding higher than that of the cofactor of the protein (Thiamine Pyrophosphate, TPP) and a synthetic analog (SUBTPP) used as reference compounds after MD Simulation. The compound was synthesized in a two-step, one-pot reaction, utilizing a non-acidic and mild oxidant to oxidize the lanosterol in order to avoid the rearrangement that accompanies the oxidation of sterols using acidic oxidants. The LAN was characterized using IR spectroscopy and NMR experiments and tested in-vivo for its antimalarial chemo suppression using a murine model with Chloroquine as a standard. The LAN at a concentration of 25 mg/kg was found to have a comparable activity with Chloroquine at 10 mg/kg and no mortality was observed among the test animals 24 days post drug administration showing that the compound indeed has potential as an antimalarial agent and a likely inhibitor of PfTk considering that there is a strong agreement between the in-silico results and biological study. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00097-8.

Network analysis, sequence and structure dynamics of key proteins of coronavirus and human host, and molecular docking of selected phytochemicals of nine medicinal plants.

The novel coronavirus of 2019 (nCoV-19) has become a pandemic, affecting over 205 nations with over 7,410,000 confirmed cases which has resulted to over 418,000 deaths worldwide. This study aimed to identify potential therapeutic compounds and phytochemicals of medicinal plants that have potential to modulate the expression network of genes that are involve in SARS-CoV-2 pathology in human host and to understand the dynamics key proteins involved in the virus-host interactions. The method used include gene network analysis, molecular docking, and sequence and structure dynamics simulations. The results identified DNA-dependent protein kinase (DNA-PK) and Protein kinase CK2 as key players in SARS-CoV-2 lifecycle. Among the predicted drugs compounds, clemizole, monorden, spironolactone and tanespimycin showed high binding energies; among the studied repurposing compounds, remdesivir, simeprevir and valinomycin showed high binding energies; among the predicted acidic compounds, acetylursolic acid and hardwickiic acid gave high binding energies; while among the studied anthraquinones and glycosides compounds, ellagitannin and friedelanone showed high binding energies against 3-Chymotrypsin-like protease (3CLpro), Papain-like protease (PLpro), helicase (nsp13), RNA-dependent RNA polymerase (nsp12), 2'-O-ribose methyltransferase (nsp16) of SARS-CoV-2 and DNA-PK and CK2alpha in human. The order of affinity for CoV proteins is 5Y3E > 6NUS > 6JYT > 2XYR > 3VB6. Finally, medicinal plants with phytochemicals such as caffeine, ellagic acid, quercetin and their derivatives could possibly remediate COVID-19.Communicated by Ramaswamy H. Sarma.

In Silico Investigation of First-Pass Effect on Selected Small Molecule Excipients and Structural Dynamics of P-glycoprotein.

In this study, the interaction of selected pharmaceutical excipients on the function of P-glycoprotein (P-gp) and activity of 6 cytochrome P450 (CYP) isoforms were computationally investigated. At binding free energy cut-off value of -5.0 kcal/mol, the result showed possible modulatory or inhibitory effect by cethyl alcohol on CPY3A4 and P-gp; cetyltrimethyl-ammonium bromide (CTAB) on CYP1A2 and P-gp; dibutyl sebacate on CYP2C9, CYP2E1, and P-gp; sodium caprylate on CYP1A2 and CYP3A4; while most of the tested excipients have good interaction with the cytochromes and P-gp. The predicted pharmacokinetics provided possible inhibitors of the CYPs and P-gp and suggested that aspartame and acetyl tributyl citrate may not permeate blood-brain barrier and not act as P-gp substrates. Target prediction for CTAB showed 100% and 35% probability of target to dynamin-1 (UniProt ID: Q05193) and histamine H3 receptor (UniProt ID: Q9Y5N1), respectively, whereas tricaprylin showed 40% probability of target to 5 Protein kinase C (UniProt IDs: P17252, Q02156, Q04759, P24723, and P05129). This study shows that synergistic effect of some excipients present in a drug formulation and multiple drugs administration is possible through modulation of CYPs activities and P-gp function, and this is crucial for consideration to mitigate toxicity in pediatric and adult populations.