Pharmacokinetic predictions and docking studies of substituted aryl amine-based triazolopyrimidine designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH)

Abstract

Background The sixteen (16) designed data set of substituted aryl amine-based triazolopyrimidine were docked against Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) employing Molegro Virtual Docker (MVD) software and their pharmacokinetic property determined through SwissADME predictor. Results The docking studies shows compound D16, 5-((6-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)amino)benzo[b]thiophen-4-ol to be the most interactive and stable derivative (re-rank score = − 114.205 kcal/mol) resulting from the hydrophobic as well as hydrogen interactions. The hydrogen interaction produced one hydrogen bond with the active residues LEU359 (H∙∙H∙∙O) at a bond distances of 2.2874 Å. All the designed derivatives were found to pass the Lipinski rule of five tests, supporting the drug-likeliness of the designed compounds. Conclusion The ADME analysis revealed a perfect concurrence with the Lipinski Ro5, where the derivatives were found to possess good pharmacokinetic properties such as molar refractivity (MR), number of rotatable bonds (nRotb), log of skin permeability (log Kp), blood-brain barrier (BBB). These results could a deciding factor for the optimization of novel antimalarial compounds.

Evaluation of therapeutic potentials of selected phytochemicals against Nipah virus, a multi-dimensional in silico study

“…The value of Gibbs free energy of solvation is derived from the ratio of Generalized-born (GB) parameters and solvent-accessible surface area in water/n-octanol (SA) (GB/SA). The iLOGP values for all the phytochemicals in this work, with exceptions to a few compounds (Stigmasterol, Beta-carotene, β-Cryptoxanthin, Lutein), were found to meet the recommended value (less than 5) (Ibrahim et al 2021 ). The extra cellular efflux of a wide range of structurally unrelated drugs is mediated by membrane-bound transporter PGP (P-glycoprotein).…”

New pyrazolyl-thiazolidinone/thiazole derivatives as celecoxib/dasatinib analogues with selective COX-2, HER-2 and EGFR inhibitory effects: design, synthesis, anti-inflammatory/anti-proliferative activities, apoptosis, molecular modelling and ADME studies

“…Also, topological polar surface area (TPSA) and the number of rotatable bonds are other critical properties that have been linked to drug bioavailability 74 . The reports suggested that compounds with a TPSA of more than 140 Å2 and more than ten rotatable bonds are thought to have low pharmacological flexibility and permeability, respectively 75 .…”

“…The molar refractivity (MR) value should be between 40 and 130 for good absorption and oral bioavailability. Acceptable molar refractivity values, in combination with the number of rotatable bonds, indicate that substances have adequate intestinal absorption and oral bioavailability 75 . Only compound 16a showed accepted MR = 126.21 m 3 /mol, but the remaining designed compound’s MR values ranging from 140.63 to 167.57 m 3 /mol, compared to the standard dasatinib (MR = 133.62 m 3 /mol).…”

Solubility and Stability of Carvedilol in Deep Eutectic Solvents: A Step Towards a Sustainable Pharmaceutical Formulation in the Liquid State

“…Both parameters are related to oral absorption capacity, and their role in medicinal chemistry has recently increased. [70] In this case, citric acid shows a greater number of hydrogen bonding sites and a higherTPSA value, indicative of greater polarity, which is slightly higher than the limit (130 Å 2 ). The rest of the studied chemicals show values in the polarity range, and choline chloride is the molecule with the lowest TPSA.…”

“…TPSA correlates with the hydrogen bonds that the molecule can establish. Both parameters are related to oral absorption capacity, and their role in medicinal chemistry has recently increased [70] . In this case, citric acid shows a greater number of hydrogen bonding sites and a higherTPSA value, indicative of greater polarity, which is slightly higher than the limit (130 Å 2 ).…”