Drug Transporters in the Kidney: Perspectives on Species Differences, Disease Status, and Molecular Docking

The kidneys are a pair of important organs that excretes endogenous waste and exogenous biological agents from the body. Numerous transporters are involved in the excretion process. The levels of these transporters could affect the pharmacokinetics of many drugs, such as organic anion drugs, organic cationic drugs, and peptide drugs. Eleven drug transporters in the kidney (OAT1, OAT3, OATP4C1, OCT2, MDR1, BCRP, MATE1, MATE2-K, OAT4, MRP2, and MRP4) have become necessary research items in the development of innovative drugs. However, the levels of these transporters vary between different species, sex-genders, ages, and disease statuses, which may lead to different pharmacokinetics of drugs. Here, we review the differences of the important transports in the mentioned conditions, in order to help clinicians to improve clinical prescriptions for patients. To predict drug-drug interactions (DDIs) caused by renal drug transporters, the molecular docking method is used for rapid screening of substrates or inhibitors of the drug transporters. Here, we review a large number of natural products that represent potential substrates and/or inhibitors of transporters by the molecular docking method.

Theoretical Evaluation of Potential Anti-Alanine Dehydrogenase Activities of Acetamide Derivatives

Tuberculosis is an airborne communicable syndrome, which has been observed to be among the top ten (10) causes of death worldwide. This work studied eleven molecular compounds via quantum chemical calculations, molecular docking method, and ADMET (absorption, distribution, metabolism, excretion, and toxicity). The selected obtained descriptors (Log P, HBA, HBD, and molecular weight) showed that the studied compounds have the ability to act drug-like. Compound D inhibited far better than the other studied ligands as well as the standard. ADMET properties of compound D proved that the predicted ADMET level was closer to the ADMET properties of the referenced drug (Isoniazid).

Investigation of potential antiviral natural products with an effect on HPV18 E6 protein by molecular docking method

Background: Infection with the Human Papillomavirus (HPV) causes cellular dysplasia, which leads to cervical cancers in women and penile or rectal cancers in men. Objective: This in silico study identified the plant compounds with potential therapeutic effects against HPV 18 oncogenic virus using the molecular docking method. Methods: The three-dimensional (3D) structure of HPV18 E6 protein, as the target protein, and the 3D structure of plant compounds with potential therapeutic effect against viruses, as ligands, was obtained from the protein databases (RCSB) and PubChem, respectively. Both structures of ligands and target protein were subjected to AutoDock tools-1.5.6, ver.4 separately. The structure with the most negative affinity was docked to reconsider its connection location. The results were analyzed more based on pharmacodynamic and pharmacokinetic parameters. Results: The docking of HPV18 E6 protein with 19 selected ligands resulted in four compounds, curcumin, silymarin, saikosaponin c, and lactupicrin, showing the best docking scores; they had better binding free energies with HPV E6 protein. Among four compounds against HPV18 E6, silymarin and curcumin were less dangerous than other compounds due to the lack of inhibition of the human Ether-à-go-go-Related Gene (hERG). Of these two compounds, silymarin had lower oral absorption, lactopicrin had less skin absorption, lactopicrin is the substrate of P-gp, and saikosaponin c crosses the blood-brain barrier. Conclusion: Among potential antiviral plants against HPV18E6, four compounds were found to be effective. According to these findings, it is recommended that in vitro and in vivo examinations be conducted to determine the effectiveness of these compounds against HPV18 Keywords: Biological products, Antiviral agents, HPV18, Molecular docking, Computational biology, E6 protein

NATURAL ISOTHIOCYANATE ANTI-MALARIA: MOLECULAR DOCKING, PHYSICOCHEMICAL, ADME, TOXICITY AND SYNTHETIC ACCESSIBILITY STUDY OF EUGENOL AND CINNAMALDEHYDE

Objective: This study aims to evaluate novel compounds of isothiocyanate (ITC) based on eugenol and cinnamaldehyde derivatives as the drug candidate of Plasmodium falciparum anti-malaria using in silico method, physicochemical, pharmacokinetics, toxicity, and synthetic accessibility prediction. This present study also describes molecular docking and pharmacoinformatics of natural ITC in Moringa oleifera leaves. Methods: A series of novel ITC compounds (3, 5, and 6) were designed and analyzed with a series of natural ITC compounds (7, 8, 9, 10) for P. falciparum anti-malaria. This research is descriptive qualitative and uses the reverse molecular docking method, proving the biological activity of compounds theoretically using software and database information. Results: Molecular docking study showed that compound 6 exhibits binding affinity (-5.3 Kcal/mol) on Van der Waals interaction with the residual active site (His159, Cys25) of cysteine protease. All designed ITC compounds are obeyed the Lipinski and Veber Rule, have a well-brain penetrant character and have a medium risk for mutagenic, tumorigenic, and reproductive prediction. They are also in the simple rate of synthetic accessibility (SA) estimation. In regards to natural ITCs, they all have better assay characteristics except the SA. Conclusion: Molecular docking, physicochemical, pharmacokinetic, and toxicity studies show that methyl eugenol isothiocyanate and cinnamaldehyde isothiocyanate are promising anti-malaria compounds. Substituents of hydroxy, acetate and tetrahydropyran groups in the building block ring are suggested for better in silico profiles enhancement.

Genetic Insight into Birt-Hogg-Dubé syndrome in Indian patients reveals novel mutations in FLCN

Background: Birt-Hogg-Dub&eacute syndrome (BHDS) is a rare monogenic condition mostly associated with germline mutations at FLCN. It is characterized by either one or more manifestations of primary spontaneous pneumothorax (PSP), skin fibrofolliculomas and renal carcinoma. Here, we comprehensively studied germline mutations in BHDS patients and asymptomatic members from 15 Indian families. Methods: Targeted amplicon NGS and Sanger sequencing was performed to detect germline mutations at FLCN in 31 clinically diagnosed patients and 74 asymptomatic family members. Functional effects and protein-protein interaction of FLCN variants were evaluated in-silico and molecular docking method. Family-based association study between pathogenic mutations and BHDS was also performed. Germline mutations at genes associated with phenotypically similar diseases were also addressed in few families. Results: Six different types of pathogenic FLCN mutations were observed in the patients. Two of them: 11-nucleotide deletion (c.1150_1160delGTCCAGTCAGC) and splice acceptor mutation (c.1301-1G>A), were novel mutations. Two unreported Clinvar pathogenic mutations: stop-gain (c.634C>T) and 4-nucleotide duplication (c.1329_1332dupAGCC), and known mutations: hotspot mutation (c.1285delC) and splice donor mutations (c.1300+1G>A) were also detected. All these mutations greatly affected the protein stability and FLCN-FNIP2 protein interaction. Family-based association studies suggested pathogenic FLCN mutations are significantly associated with BHDS. Two pathogenic SNPs, rs1801133 and rs138189536, at MTHFR, associated with Homocystinuria, were found in one family. Conclusion: Pathogenic mutations at FLCN may play key roles in deregulating metabolic pathways leading to disease pathogenesis. Instead of FLCN mutations, MTHFR pathogenic SNPs were also detected in clinically diagnosed BHDS patients, therefore, genetic evaluation is necessary to avoid confounding diagnosis.

PLANT SUBSTANCES AS POTENTIAL SOURCE OF ORIGINAL ANTI-VIRUS AGENTS

This article summarizes the literature data and the results of our own studies on the search for antiviral compounds based on terpenoids, flavonoids, alkaloids. New bimolecular and ketoamide derivatives based on sesquiterpene γ-lactones arglabin, grossheimin and α-santonin were synthesized in quantitative yields up to 80%. The molecular docking method was used to study the “structure-activity” relationship of natural compounds and their derivatives in relation to SARS-Cov-2. The results obtained in silico demonstrated that sesquiterpene γ-lactones and their derivatives inhibit the SARS-Cov-2 spike protein and proteases, as well as the angiotensin-converting enzyme 2. The identified molecules can be considered as candidates for the development of new drugs with antiviral activity on their basis.

THE POTENTIAL INHIBITION OF XANTHINE OXIDASE BY PHENOLIC AND FLAVONOIDS DATE (Phoenix dactylifera) WITH MOLECULAR DOCKING METHOD

Dates is fruit of palm trees that mostly grow in the Middle East. Dates contain phenolic acids and flavonoids that have antioxidants and potentially inhibit the ability of xanthine oxidase. The purpose of this research to determine the molecular interactions of xanthine oxidase by ligand of phenolic acids and flavonoids to inhibiting the production of uric acid. This research was conducted by site directed docking method. The size of the center of retardation used in this research is x = 26.569, y = 9.985, and z = 113.088 and the retardation volume of x = 14, y = 14, and z = 16. Inhibition by flavonoid and phenolic acid compounds has produces good inhibition strength shown by Gibbs free energy which is negative. The compound with the highest Gibbs free energy value is the anthocyanins compound which is -7.3 kCal / mol, the value is higher than the comparator ligand, allopurinol. Based on the bond analysis that is formed, the best compound in inhibiting xanthine oxidase is syringic acid.

Anti-human acute leukemia, cytotoxicity, antioxidant, and collagenase and aldose reductase inhibition effects of 2′-Hydroxy-4′,5′-dimethoxyacetophenone in the in vitro condition

IntroductionIn this study, it is recorded the inhibition effect of 2′-Hydroxy-4′,5′-dimethoxyacetophenone on aldose reductase and collagenase enzymes. Also, we have investigated that the in vitro inhibition effects of 2′-Hydroxy-4′,5′-dimethoxyacetophenone on aldose reductase and collagenase enzymes.Material and methodsTo investigate the antioxidant effects of 2′-Hydroxy-4′,5′-dimethoxyacetophenone, the DPPH test was used in the presence of butylated hydroxytoluene as the positive control. MTT test was used on normal (HUVEC) and human acute leukemia (32D-FLT3-ITD, Human HL-60/vcr, MOLT-3, and TALL-104) cell lines. 2′-Hydroxy-4′,5′-dimethoxyacetophenone had high cell death and anti-human acute leukemia effects against 32D-FLT3-ITD, Human HL-60/vcr, MOLT-3, and TALL-104 cell lines.ResultsThe 2′-Hydroxy-4′,5′-dimethoxyacetophenone inhibited half of the DPPH molecules in the concentration of 157 µg/mL. Among the above cell lines, the best result of anti-human acute leukemia properties of silver nanoparticles was gained in the cell line of UM-UC-3. The results of this study indicated the excellent anti-human acute leukemia potentials of 2′-Hydroxy-4′,5′-dimethoxyacetophenone in the in vitro condition.ConclusionsAfter confirming the above results in the clinical trial researches, this formulation may be administrated for the treatment of several types of acute leukemia in humans. After that, the comparison of the biological activities of the 2′-Hydroxy-4′,5′-dimethoxyacetophenone molecule against the studied enzymes was done by molecular docking method.

Computational drug repurposing study of antiviral drugs against main protease, RNA polymerase, and spike proteins of SARS-CoV-2 using molecular docking method

Objectives The new Coronavirus (SARS-CoV-2) created a pandemic in the world in late 2019 and early 2020. Unfortunately, despite the increasing prevalence of the disease, there is no effective drug for the treatment. A computational drug repurposing study would be an appropriate and rapid way to provide an effective drug in the treatment of the coronavirus disease of 2019 (COVID-19) pandemic. In this study, the inhibitory potential of more than 50 antiviral drugs on three important proteins of SARS-CoV-2, was investigated using the molecular docking method. Methods By literature review, three important proteins, including main protease, RNA-dependent RNA polymerase (RdRp), and spike, were selected as the drug targets. The three-dimensional (3D) structure of protease, spike, and RdRp proteins was obtained from the Protein Data Bank. Proteins were energy minimized. More than 50 antiviral drugs were considered as candidates for protein inhibition, and their 3D structure was obtained from Drug Bank. Molecular docking settings were defined using Autodock 4.2 software and the algorithm was executed. Results Based on the estimated binding energy of docking and hydrogen bond analysis and the position of drug binding, five drugs including, indinavir, lopinavir, saquinavir, nelfinavir, and remdesivir, had the highest inhibitory potential for all three proteins. Conclusions According to the results, among the mentioned drugs, saquinavir and lopinavir showed the highest inhibitory potential for all three proteins compared to the other drugs. This study suggests that saquinavir and lopinavir could be included in the laboratory phase studies as a two-drug treatment for SARS-CoV-2 inhibition.