Current Drug Metabolism - Volume 22, Issue 7, 2021

In the drug discovery setting, undesirable ADMET properties of a pharmacophore with good predictive power obtained after a tedious drug discovery and development process may lead to late-stage attrition. The earlystage ADMET profiling has brought a new dimension to lead drug development. Although several high-throughput in vitro models are available for ADMET profiling, the in silico methods are gaining more importance because of their economic and faster prediction ability without the requirements of tedious and expensive laboratory resources. Nonetheless, in silico ADMET tools alone are not accurate, and therefore, ideally adopted along with in vitro and or in vivo methods in order to enhance the predictability power. This review summarizes the significance and challenges associated with the application of in silico tools as well as the possible scope of in vitro models for integration to improve the ADMET predictability power of these tools.

Membrane transporters play an important role in intestinal absorption, distribution and clearance of drugs. Additionally transporters along with enzymes regulate tissue exposures (e.g. liver, kidney and brain), which are important for safety and efficacy considerations. Early identification of transporters involved guides generation of in vitro and in vivo data needed to gain mechanistic understanding on the role of transporters in organ clearance, tissue exposures and enables development of physiological-based pharmacokinetic (PBPK) models. A lot of progress has been made in developing several in vitro assay systems and mechanistic in silico models to determine kinetic parameters for transporters, which are incorporated into PBPK models. Although, intrinsic clearance and inhibition data from in vitro systems generally tend to underpredict in vivo clearance and magnitude of drug-drug interactions (DDIs), empirical scaling factors derived from a sizable dataset are often used to offset underpredictions. PBPK models are increasing used to predict the impact of transporters on intestinal absorption, clearance, victim and perpetrator DDIs prior to first in human clinical trials. The models are often refined when clinical data is available and are used to predict pharmacokinetics in untested scenarios such as the impact of polymorphisms, ontogeny, ethnicity, disease states and DDIs with other perpetrator drugs. The aim of this review is to provide an overview of (i) regulatory requirements around transporters, (ii) in vitro systems and their limitations in predicting transporter mediated drug disposition and DDIs, (iii) PBPK modelling tactics and case studies used for internal decision making and/or for regulatory submissions.

Background: Recently, a series of 15 compounds with 2,4,5-trisubstitutedthiazole scaffold having 2- amino/amido/ureido functional groups attached with 5-aryl and 4-carboxylic acid/ester groups (1-15) were reported from our research group as novel potential inhibitors of carbonic anhydrase III (CA III) enzyme. Several research studies revealed the potential role of CA inhibitors as anticancer agents, giving us the impetus to further explore these compounds for their potential as anticancer agents. Objectives: The objective of this study is to investigate the potential of 2,4,5-trisubstitutedthiazole derivatives (1-15) for their possible cytotoxic activity (in vitro), and to calculate (in silico) the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties to evaluate the drug-likeness of these compounds. Methods: Cytotoxic activity (in vitro) was carried out on two breast cancer cell lines (MCF7 and MDA231), and the lymphoblastoid human erythroleukemia cell line (K562) using 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. Doxorubicin was used as a positive control. ADMET properties were calculated (in silico) using the QikProp module of Schrodinger. Results: Compounds 6 and 9 with a phenylureido group at 2-position, and a methyl-carboxylate moiety at 4-position having para-tolyl and benzyl moiety, respectively at the 5-position of the thiazole ring showed significant cytotoxicity against all the three cell lines. In particular, compound 6 with para-tolyl group at 5-position exhibited the most potent inhibitory effect on the viability of MCF7, MDA231 and K562 cells, with IC50 values of 22, 26 and 11 μM, respectively. Notably, all the highly active compounds possess a phenyluriedo group at 2-- position with a methyl ester group at 4-position, indicating the probable role of these substituents in the target interaction and inducing cytotoxicity. Interestingly, compounds 1-4 and 10-13 with a free amino group at 2-position did not show any cytotoxic effect on the K562 cell line, while exhibiting mild to moderate cytotoxicity against the MCF7 and MDA231 cell lines. However, none of the tested compounds showed any activity against normal human dermal fibroblast cells indicating the safety/tolerability of the examined concentrations. Furthermore, these compounds also exhibited satisfactory ADMET properties (in silico), without violating Lipinski’s rule of five. Conclusion: The most active compounds 6 and 9 predicted to have good oral absorption and low human serum protein binding, exhibiting no reactive functional group and probable CNS activity compared with 95% of the known oral drugs as predicted (in silico) by QikProp. Thus, compounds 6 and 9 can be considered as lead molecules for further modification and discovery of novel anticancer agents with nanomolar potency.

Aims: This study aimed at studying various types of gynecological cancers and the available therapeutics to investigate safe and effective drugs. Background: Cancer is the most common cause of mortality throughout the world. When the statistics are being considered for gynecological cancers, ovarian, cervical, and uterine cancers are among the most prevalent types. They have the worst prognosis and the highest mortality rate and by the year 2040 significant increase in mortality rate is predicted. Objective: The major limitation with the development of anti-cancer therapeutics for gynecological cancers is the safety of the therapeutics for the developing fetus as well as the mother. Various medicinal classes of natural to synthetic therapeutics have been reported including kinase inhibitors as the most promising category of anti-cancer drugs. Methods: A dataset of kinase inhibitors clinically approved as anticancer agents was derived through a literature review. A QSAR based approach i.e. VEGAQSAR has been applied to evaluate the reproductive and developmental toxicity for the selected class of kinase inhibitors. Result: In the present work, the promising category of anticancer kinase inhibitors has been investigated for its toxicity potential with the help of in silico approach. The anti-cancer kinase inhibitors were categorized based on the found non-toxic or toxic properties towards reproductive and developmental toxicity. Conclusion: Early prediction of the available or proposed anti-cancer therapeutics for their contribution towards developmental and reproductive toxicity is an important criterion for their use in pregnancy-associated cancers. The investigation of the toxicity profile of available anti-cancer kinase therapeutics will be helpful to design and develop novel and safe anti-cancer drugs in the near future. The study outcomes will benefit the current anticancer drug development efforts.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that exerts a huge burden on our society. The occurrence of this neurodegenerative disease has been increasing day-by-day. PD can be a serious concern if the patients are left untreated. However, conventional treatment has many side-effects and less bioavailability in the brain. Therefore, the necessary measurement is required to solve the limitations of PD treatment. Nanotechnology has made a major contribution to comprehend PD pathogenesis. Nanotechnology can provide efficient therapies that have reduced side-effects and increased bioavailability in the brain. This review emphasizes the emerging promise of nanoparticle-based treatment, drug delivery, and other therapeutic approaches for PD. Besides, the advantages of different approaches on nanotechnology platforms are far better over conventional therapy in the treatment of PD.

Background: The underlying cause of major neurodegenerative disorders remains a healthcare mystery. The thoroughly investigated causes include oxidative stress, inflammation, environmental factor, mitochondrial dysfunction, and irregular neuronal protein aggregation. Withania somnifera has been used for more than 2500 years as a useful medicinal plant to improve disease defense, prevent aging, rejuvenate the body in a vulnerable situation, and generate a feeling of mental well-being. However, a persuasive paper emphasizing its neuroprotective nature is missing. Objective: In the current review, we have delineated the protective role of W. somnifera against various neurological disorders and its progress in delivery systems. Methods: The database used in the retrieval of data were PubMed, Scopus, Science direct, and SciFinder. The keywords used were W. somnifera, Ashwagandha, neuroprotective activities, etc. The principal source of the data retrieval includes research articles, review papers, and short communications from reputed publishers, including the New England Journal of Medicine, Elsevier, Nature, Springer, and Taylor & Francis. Results: After an extensive literature review, we found that W. somnifera mitigates various neurological disorders, including Parkinson's disease, Alzheimer's disease, Huntington disease, tardive dyskinesia, stroke, and anxiety. Furthermore, natural compounds in nano sizes range possess better neuroprotective activity. Consequently, polymeric nanomicelles, nanoparticles, and nanofibers of natural products are used in the treatment of neurodegenerative diseases. Conclusion: The current review substantially deciphered the protective role of W. somnifera against various neurological disorders. However, future studies are further required better to understand the molecular mechanisms behind their neuroprotective nature.

Aim & Background: Ornidazole is an antimicrobial drug used to treat certain types of vaginal, urinary tract, and interstitial infections. The study aims to formulate and evaluate the dental inserts by using a drug candidate to sustained drug release to improve patient compliance, reduce dosing frequency, reduce the risk of dose dumping, and avoid the first-pass metabolism. They have better therapeutic efficacy and fewer side effects. Methods: The dental inserts were prepared using various polymers alone and in combination with the different ratios of polymers. The evaluation parameters like thickness, drug content, content uniformity, moisture reuptake, weight variation, swelling studies, and erosion studies of the optimized inserts were studied. The in-vivo studies were conducted to determine the reduction of pocket depth in human volunteers. Results: The system containing ethylcellulose and hydroxyl methyl propyl cellulose K100M (4:1) formulation F6 was optimized because drug release was sustained up to 120 hrs concerning other formulations. Optimized formulation followed first-order kinetics and Peppas release kinetics via fickian diffusion. There was no swelling, itching, irritation, and no reduction in the pocket depth in in-vivo studies. Conclusion: The study concluded that dental inserts could extend the release of Ornidazole for many hours and also enhance bioavailability. Furthermore, they also help in avoiding the first-pass effect. In vivo studies’ observations showed no itching, irritation, swelling, and pocket-depth reduction.