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Promises of Molecular Pharmaceutics in the Development of Novel Drug Delivery Formulations

Kumar P, Chaudhary B, Jain V, Baboota S, Shivanandy P, Alharbi KS, et al.

Curr Drug Deliv, 2023;20(9):1262-1274.
PMID: 36380413 DOI: 10.2174/1567201820666221114113637

Molecular pharmaceutics play a critical role in the drug delivery system, representing the direct interconnection of drug bioavailability with its molecular form. There is a diversity in the molecular structures by which it affects its properties, such as amorphous form, crystalline form, partialamorphous molecular dispersion, and disordered state. The active pharmaceutical ingredient (API) and the excipients utilized in the formulation process contain various divergent modes used in the formulation process. They include better formulations of any type to obtain good quality pharmaceutical products. This review reveals how the molecular states affect the API and are important in maintaining the quality of dosage forms. Furthermore, the physio-chemical properties of the components and various pharmaceutical approaches employed in the formulation of dosage forms are studied from the point of view of molecular pharmaceutics.
New biologically dynamic hybrid pharmacophore triazinoindole-based-thiadiazole as potent α-glucosidase inhibitors: In vitro and in silico study

Khan AA, Rahim F, Taha M, Rehman W, Iqbal N, Wadood A, et al.

Int J Biol Macromol, 2022 Feb 28;199:77-85.
PMID: 34968547 DOI: 10.1016/j.ijbiomac.2021.12.147

Triazinoindole bearing thiadiazole derivatives (1-25) have been synthesized and characterized through different spectroscopic techniques such as 1H, 13C-NMR and HREI-MS. The purpose of the study was to investigate the anti-diabetic activity of the synthesized triazinoindole bearing thiadiazole derivatives by inhibition of α-glucosidase. All synthesized analogues showed outstanding inhibition of α-glucosidase enzyme with IC50 values ranging from 2.5 ± 0.10 to 38.10 ± 0.10 µM as compared to the standard drug acarbose (IC50 = 38.45 ± 0.80 µM). Analogue 4 (IC50 = 2.5 ± 0.10 µM) was identifies as the most potent analogue in the series with fifteen folds more active than standard acarbose. Structure activity relationship (SAR) studies suggested that α-glucosidase activities of triazinoindole bearing thiadiazole are primarily dependent upon on number and position of different substitutions present on phenyl parts. Molecular docking study were conducted of the optimized compounds (i.e., compound 4, 6, and 3 etc. using MOE default parameters), the results revealed that compound 4, 6, and 3 showed numerous key interactions with the target protein, which indicate the high potential of these compounds against the target compound. All these compounds were screened for cytotoxic activity against normal normal Vero cell line and found non-toxic.
Role of Flavonoids in Management of Various Biological Targets in Alzheimer's Disease: Evidence from Preclinical to Clinical Studies

Alharbi KS, Javed Shaikh MA, Imam SS, Alshehri S, Ghoneim MM, Almalki WH, et al.

Curr Med Chem, 2023;30(18):2061-2074.
PMID: 36415096 DOI: 10.2174/0929867330666221122115212

More than 10 million people worldwide have Alzheimer's disease (AD), a degenerative neurological illness and the most prevalent form of dementia. AD's progression in memory loss, cognitive deterioration, and behavioral changes are all symptoms. Amyloid-beta 42 (Aβ42), the hyperphosphorylated forms of microtubule-associated tau protein, and other cellular and systemic alterations are all factors that contribute to cognitive decline in AD. Rather than delivering a possible cure, present therapy strategies focus on reducing disease symptoms. It has long been suggested that various naturally occurring small molecules (plant extract products and microbiological isolates, for example) could be beneficial in preventing or treating disease. Small compounds, such as flavonoids, have attracted much interest recently due to their potential to alleviate cellular stress. Flavonoids have been proven helpful in various ways, including antioxidants, anti-inflammatory agents, and anti-apoptotic agents, but their mechanism remains unknown. The flavonoid therapy of Alzheimer's disease focuses on this review, which includes a comprehensive literature analysis.
Fulltext Recent Developments in Diagnosis of Epilepsy: Scope of MicroRNA and Technological Advancements

Bandopadhyay R, Singh T, Ghoneim MM, Alshehri S, Angelopoulou E, Paudel YN, et al.

Biology (Basel), 2021 Oct 25;10(11).
PMID: 34827090 DOI: 10.3390/biology10111097

Epilepsy is one of the most common neurological disorders, characterized by recurrent seizures, resulting from abnormally synchronized episodic neuronal discharges. Around 70 million people worldwide are suffering from epilepsy. The available antiepileptic medications are capable of controlling seizures in around 60-70% of patients, while the rest remain refractory. Poor seizure control is often associated with neuro-psychiatric comorbidities, mainly including memory impairment, depression, psychosis, neurodegeneration, motor impairment, neuroendocrine dysfunction, etc., resulting in poor prognosis. Effective treatment relies on early and correct detection of epileptic foci. Although there are currently a few well-established diagnostic techniques for epilepsy, they lack accuracy and cannot be applied to patients who are unsupportive or harbor metallic implants. Since a single test result from one of these techniques does not provide complete information about the epileptic foci, it is necessary to develop novel diagnostic tools. Herein, we provide a comprehensive overview of the current diagnostic tools of epilepsy, including electroencephalography (EEG) as well as structural and functional neuroimaging. We further discuss recent trends and advances in the diagnosis of epilepsy that will enable more effective diagnosis and clinical management of patients.
PI3K/Akt/mTOR Pathways Inhibitors with Potential Prospects in Non-Small-Cell Lung Cancer

Alharbi KS, Shaikh MAJ, Almalki WH, Kazmi I, Al-Abbasi FA, Alzarea SI, et al.

J Environ Pathol Toxicol Oncol, 2022;41(4):85-102.
PMID: 36374963 DOI: 10.1615/JEnvironPatholToxicolOncol.2022042281

Lung cancer is the leading cause of cancer-related mortality across the globe. The most prevalent pathological form of lung cancer is non-small-cell lung cancer (NSCLC). Elevated stimulation of the PI3K/Akt/mTOR pathway causes a slew of cancer-related symptoms, making it a promising target for new anticancer drugs. The PI3K/Akt/mTOR path is involved extensively in carcinogenesis and disease advancement in NSCLC. Several new inhibitors targeting this pathway have been discovered in preclinical investigations and clinical trials. The etiology and epidemiology of NSCLC and biology of the PI3K/Akt/mTOR cascade and its role in NSCLC pathogenesis have all been discussed in this article. In this article, we've reviewed PI3K/Akt/mTOR cascade inhibitors that have been proven in vitro and in preclinical trials to be effective in NSCLC. Drugs targeting the PI3K/Akt/mTOR path in the treatment of NSCLC were also addressed. A better knowledge of the underlying molecular biology, including epigenetic changes, is also critical to detecting relevant biomarkers and guiding combination methods. Additionally, improved clinical trial designs will increase the capacity to test novel drugs and combinations for accounting for genomic variation and eventually improve patient outcomes.
Fulltext Novel Phenolic Compounds as Potential Dual EGFR and COX-2 Inhibitors: Design, Semisynthesis, in vitro Biological Evaluation and in silico Insights

Abdelgawad MA, Musa A, Almalki AH, Alzarea SI, Mostafa EM, Hegazy MM, et al.

Drug Des Devel Ther, 2021;15:2325-2337.
PMID: 34103896 DOI: 10.2147/DDDT.S310820

Introduction: Epidermal growth factor receptor (EGFR) inhibition is an imperative therapeutic approach targeting various types of cancer including colorectal, lung, breast, and pancreatic cancer types. Moreover, cyclooxygenase-2 (COX-2) is frequently overexpressed in different types of cancers and has a role in the promotion of malignancy, apoptosis inhibition, and metastasis of tumor cells. Combination therapy has been emerged to improve the therapeutic benefit against cancer and curb intrinsic and acquired resistance.
Methods: Three semi-synthetic series of compounds (C1-4, P1-4, and G1-4) were prepared and evaluated biologically as potential dual epidermal growth factor receptor (EGFR) and COX-2 inhibitors. The main phenolic constituents of Amaranthus spinosus L. (p-coumaric, caffeic and gallic) acids have been isolated and subsequently subjected to diazo coupling with various amines to get novel three chemical scaffolds with potential anticancer activities.
Results: Compounds C4 and G4 showed superior inhibitory activity against EGFR (IC50: 0.9 and 0.5 µM, respectively) and displayed good COX-2 inhibition (IC50: 4.35 and 2.47 µM, respectively). Moreover, the final compounds were further evaluated for their cytotoxic activity against human colon cancer (HT-29), pancreatic cancer (PaCa-2), human malignant melanoma (A375), lung cancer (H-460), and pancreatic ductal cancer (Panc-1) cell lines. Interestingly, compounds C4 and G4 exhibited the highest cytotoxic activity with average IC50 values of 1.5 µM and 2.8 µM against H-460 and Panc-1, respectively. The virtual docking study was conducted to gain proper understandings of the plausible-binding modes of target compounds within EGFR and COX-2 binding sites.
Discussion: The NMR of prepared compounds showed characteristic peaks that confirmed the structure of the target compounds. The synthesized benzoxazolyl scaffold containing compounds showed inhibitory activities for both COXs and EGFR which are consistent with the virtual docking study.
In silico development of potential InhA inhibitors through 3D-QSAR analysis, virtual screening and molecular dynamics

Bhaskar V, Kumar S, Sujathan Nair A, Gokul S, Rajappan Krishnendu P, Benny S, et al.

J Biomol Struct Dyn, 2023 Dec 08.
PMID: 38064315 DOI: 10.1080/07391102.2023.2291549

Tuberculosis is one of the most ancient infectious diseases known to mankind predating upper Paleolithic era. In the current scenario, treatment of drug resistance tuberculosis is the major challenge as the treatment options are limited, less efficient and more toxic. In our study we have developed an atom based 3D QSAR model, statistically validated sound with R2 > 0.90 and Q2 > 0.72 using reported direct inhibitors of InhA (2018-2022), validated by enzyme inhibition assay. The model was used to screen a library of 3958 molecules taken from Binding DB and candidates molecules with promising predicted activity value (pIC50) > 5) were selected for further analyzed screening by using molecular docking, ADME profiling and molecular dynamic simulations. The lead molecule, ZINC11536150 exhibited good docking score (glideXP = -11.634 kcal/mol) compared to standard triclosan (glideXP = -7.129 kcal/mol kcal/mol) and through molecular dynamics study it was observed that the 2nv6-complex of ZINC11536150 with Mycobacterium tuberculosis InhA (PDB entry: 2NV6) complex remained stable throughout the entire simulation time of 100 ns.Communicated by Ramaswamy H. Sarma.