Recent Advances in the Treatment and Management of Alzheimer's Disease: A Precision Medicine Perspective.

About 60% to 70% of people with dementia have Alzheimer's Disease (AD), a neuro-degenerative illness. One reason for this disorder is the misfolding of naturally occurring proteins in the human brain, specifically ß-amyloid (Aß) and tau. Certain diagnostic imaging techniques, such as amyloid PET imaging, tau PET imaging, Magnetic Resonance Imaging (MRI), Comput-erized Tomography (CT), and others, can detect biomarkers in blood, plasma, and cerebral spinal fluids, like an increased level of ß-amyloid, plaques, and tangles. In order to create new pharma-cotherapeutics for Alzheimer's disease, researchers must have a thorough and detailed knowledge of amyloid beta misfolding and other related aspects. Dolopezil, rivastigmine, galantamine, and other acetylcholinesterase inhibitors are among the medications now used to treat Alzheimer's disease. Another medication that can temporarily alleviate dementia symptoms is memantine, which blocks the N-methyl-D-aspartate (NMDA) receptor. However, it is not able to halt or re-verse the progression of the disease. Medication now on the market can only halt its advance-ment, not reverse it. Interventions to alleviate behavioral and psychological symptoms, exhibit an-ti-neuroinflammation and anti-tau effects, induce neurotransmitter alteration and cognitive en-hancement, and provide other targets have recently been developed. For some Alzheimer's pa-tients, the FDA-approved monoclonal antibody, aducanumab, is an option; for others, phase 3 clinical studies are underway for drugs, like lecanemab and donanemab, which have demonstrat-ed potential in eliminating amyloid protein. However, additional study is required to identify and address these limitations in order to reduce the likelihood of side effects and maximize the thera-peutic efficacy.

Assessment of structural and activity-related contributions of various PIM-1 kinase inhibitors in the treatment of leukemia and prostate cancer.

One of the most perilous illnesses in the world is cancer. The cancer may be associated with the mutation of different genes inside the body. The PIM kinase, also known as the serine/threonine kinase, plays a critical role in the biology of different kinds of cancer. They are widely distributed and associated with several biological processes, including cell division, proliferation, and death. Aberration of PIM-1 kinase is found in varieties of cancer. Prostate cancer and leukemia can both be effectively treated with PIM-1 kinase inhibitors. There are several potent compounds that have been explored in this review based on heterocyclic compounds for the treatment of prostate cancer and leukemia that have strong effects on the suppression of PIM-1 kinase. The present review summarizes the PIM-1 kinase pathway, their inhibitors under clinical trial, related patents, and SAR studies of several monocyclic, bicyclic, and polycyclic compounds. The study related to their molecular interactions with receptors is also included in the present manuscript. The study may be beneficial to scientists for the development of novel compounds as PIM-1 inhibitors in the treatment of prostate cancer and leukemia.

Structural Perspectives in the Development of Novel EGFR Inhibitors for the Treatment of NSCLC.

Non-small cell Lung cancer (NSCLC) is the most common type of lung cancer, which is caused by high consumption of tobacco and smoking. It is an epithelial lung cancer that affects about 2.2 million people across the globe, according to International Agency for Research on Cancer (IARC). Non-small cell lung cancer is a malignant tumor caused by EGFR mutation that occurs in the in-frame deletion of exon 19 and L858R point mutation in exon 21. Presently, clinically available inhibitors of EGFR (including erlotinib, lapatinib, gefitinib, selumetinib, etc.) are not specific and responsible for undesirable adverse effects. Moreover, to solve this problem search for newer EGFR inhibitors is the utmost need for the treatment and/or management of increasing lung cancer burden. The discovery of therapeutic agents that inhibit the specific target in tumorous cells, such as EGFR, is one of the successful strategies in treating many cancer therapies, including lung cancer. The exhaustive literature survey (2018-2023) has shown the importance of medicinally privileged pyrimidine derivatives together, fused and/or clubbed with other heterocyclic rings to design and develop novel EGFR inhibitors. Pyrimidine derivatives substituted with phenylamine, indole, pyrrole, piperazine, pyrazole, thiophene, pyridine and quinazoline derivatives substituted with phenylamine, pyrimidine, morpholine, pyrrole, dioxane, acrylamide, indole, pyridine, furan, pyrimidine, pyrazole etc. are privileged heterocyclic rings shown promising activity by inhibiting EGFR and TKIs. The present review summarizes the structure-activity relationship (SAR) and enzyme inhibitory activity, including IC50 values, percentage inhibition, and kinetic studies of potential compounds from various literature. The review also includes various aspects of molecular docking studies with compounds under clinical trials and patents filed on pyrimidine-based EGFR inhibitors in treating non-small cell lung cancer. The present review may benefit the medicinal chemist for developing novel compounds such as EGFR inhibitors.

A comprehensive review of small molecules targeting PI3K pathway: Exploring the structural development for the treatment of breast cancer.

Cancer stands as one of the deadliest diseases, ranking second in terms of its global impact. Despite the presence of numerous compelling theories concerning its origins, none have succeeded in fully elucidating the intricate nature of this ailment. Among the prevailing concerns in today's world, breast cancer proliferation remains a significant issue, particularly affecting females. The abnormal proliferation of the PI3K pathway emerges as a prominent driver of breast cancer, underscoring its role in cellular survival and proliferation. Consequently, targeting this pathway has emerged as a leading strategy in breast cancer therapeutics. Within this context, the present article explores the current landscape of anti-tumour drug development, focusing on structural activity relationships (SAR) in PI3K targeting breast cancer treatment. Notably, certain moieties like triazines, pyrimidine, quinazoline, quinoline, and pyridoxine have been explored as potential PI3K inhibitors for combating breast cancer. Various heterocyclic small molecules are undergoing clinical trials, such as Alpelisib, the first orally available FDA-approved drug targeting PI3K; others include buparlisib, pictilisib, and taselisib, which inhibit class I PI3K. These drugs are used for the treatment of breast cancer but still have various side effects with their high cost. Therefore, the primary goal of this review is to include all current advances in the development of anticancer medicines that target PI3K over-activation in the treatment of breast cancer.

Multistage in silico approach to identify novel quinoline derivatives as potential c-kit kinase inhibitors.

The type II-C-KIT signaling network has been extensively studied for its potential as a target for cancer treatment, leading to the investigation of quinoline derivatives as compounds with inhibitory effects on c-Kit kinase. In this study, a multistage approach was employed, including the creation of pharmacophore models, 3D QSAR analysis, virtual screening, docking investigations, and molecular dynamics stimulation. The pharmacophore evaluation included a data set of 29 ligands, which resulted in the generation of the ADDHR_1pharmacophore model as the most promising, with a survival score of 5.6812. The main objective was to utilize the atom-based 3D-QSAR approach for generating robust 3D-QSAR models aimed at identifying new TypeII-C-kit kinase inhibitors. The evaluations of these models have convincingly demonstrated their high predictive power (Q2 = 0.6547, R2 = 0.9947). Using atom-based 3D-QSAR data, a total of 7564 novel compounds were generated from R-group enumeration. Molecular docking and MM-GBSA study revealed that compound A1 exhibited the highest binding score of -9.30 kcal/mol and a Δ GBind value of -90.56 kcal/mol. The ZINC compounds were then screened using the pharmacophore model, followed by virtual screening, which identified ZINC65798256, ZINC09317958, ZINC73187176, and ZINC76176670 as potential candidates with promising docking scores. Among these, ZINC65798256 demonstrated the best binding interactions with amino acid residues, ASP810, LYS623, CYS673, and THR670 (PDB ID: 1T46). To further analyze the structural features and molecular interactions, molecular dynamics simulation was conducted for a time scale of 100 ns.Communicated by Ramaswamy H. Sarma.

Integrated fragment-based drug design and virtual screening techniques for exploring the antidiabetic potential of thiazolidine-2,4-diones: Design, synthesis and in vivo studies.

Diabetes mellitus is a metabolic disorder characterized by elevated blood sugar levels and related complications. This study focuses on harnessing and integrating fragment-based drug design and virtual screening techniques to explore the antidiabetic potential of newly synthesized thiazolidine-2,4-dione derivatives. The research involves the design of novel variations of thiazolidine-2,4-dione compounds by Fragment-Based Drug Design. The screening process involves pharmacophore based virtual screening through docking algorithms, and the identification of newly twelve top-scoring compounds. The molecular docking analysis revealed that compounds SP4e, SP4f showed highest docking scores of -9.082 and -10.345. The binding free energies of the compounds SP4e, SP4f and pioglitazone was found to be -19.9, -16.1 and -13 respectively, calculated using the Prime MM/GBSA approach. The molecular dynamic study validates the docking results. Furthermore, In the Swiss albino mice model, both SP4e and SP4f exhibited significant hypoglycaemic effects, comparable to the reference drug pioglitazone. Furthermore, these compounds demonstrated favorable effects on the lipid profile, reducing total cholesterol, triglycerides, and LDL levels while increasing HDL levels. In mice tissue, the disease control group showed PPAR-γ expression of 4.200 ± 0.24, while compound SP4f displayed higher activation at 7.84 ± 0.431 compared to compound SP4e with an activation of 7.68 ± 0.65. In zebrafish model, SP4e and SP4f showed significant reductions in blood glucose levels and lipid peroxidation, along with increased glutathione levels and catalase activity. These findings highlighted the potential of SP4e and SP4f as antidiabetic agents, warranting further exploration for therapeutic applications. The in vitro study was performed in HEK-2 cell line, the pioglitazone group demonstrated PPAR-γ expression of EC50 = 575.2, while compound SP4f exhibited enhanced activation at EC50 = 739.0 in contrast to compound SP4e activation of EC50 = 826.7.

An insight on medicinal attributes of 1,2,3- and 1,2,4-triazole derivatives as alpha-amylase and alpha-glucosidase inhibitors.

Diabetes Mellitus (DM) is the globe's common leading disease which is caused by high consumption of glucose. DM compiles groups of metabolic disorders which are characterized by inadequate secretion of insulin from pancreas, resulting in hyperglycemia condition. Many enzymes play a vital role in the metabolism of carbohydrate known as α-amylase and α-glucosidase which is calcium metalloenzyme that leads to breakdown of complex polysaccharides into glucose. To tackle this problem, search for newer antidiabetic drugs is the utmost need for the treatment and/or management of increasing diabetic burden. The inhibition of α-amylase and α-glucosidase is one of the effective therapeutic approaches for the development of antidiabetic therapeutics. The exhaustive literature survey has shown the importance of medicinally privileged triazole specifically 1,2,3-triazol and 1,2,4-triazoles scaffold tethered, fused and/or clubbed with other heterocyclic rings structures as promising agents for designing and development of novel antidiabetic therapeutics. Molecular hybrids namely pyridazine-triazole, pyrazoline-triazole, benzothiazole-triazole, benzimidazole-triazole, curcumin-triazole, (bis)coumarin-triazole, acridine-9-carboxamide linked triazole, quinazolinone-triazole, xanthone-triazole, thiazolo-triazole, thiosemicarbazide-triazole, and indole clubbed-triazole are few examples which have shown promising antidiabetic activity by inhibiting α-amylase and/or α-glucosidase. The present review summarizes the structure-activity relationship (SAR), enzyme inhibitory activity including IC50 values, percentage inhibition, kinetic studies, molecular docking studies, and patents filed of the both scaffolds as alpha-amylase and alpha-glucosidase inhibitors, which may be used for further development of potent inhibitors against both enzymes.

A Mini-review on Recent Strategies and Applications of Nanomedicines to Combat Antimicrobial Resistance.

One of the key factors contributing to mortality and morbidity globally is infectious ailments. According to recent statistics from WHO, amplified antimicrobial resistance occurrence among bacteria signifies the utmost threat to global public health. Bacteria have developed various strategies to resist antimicrobials, including enzymatic inactivation of antibiotics, drug efflux, modifications of the antibiotic molecule or chemical alteration of the antibiotic, limited drug uptake, etc. Furthermore, the inefficiency of antimicrobial drugs against resistant bacteria due to low solubility, instability, and associated side effects augments challenges to combat these resistant pathogens. This has attracted the attention of researchers to create nano-delivery and targeting techniques. This review presents an overview of antimicrobial resistance (AMR), its various subtypes, as well as mechanisms involved in AMR. This review also describes current strategies and applications of various nanocarriers, including nanoparticles, liposomes, lipid-based nanoparticles, micelles, and polymeric nanoparticles.

Design, synthesis and antidiabetic study of triazole clubbed indole derivatives as α-glucosidase inhibitors.

α -Glucosidase is an enzyme present near the brush boundary of the small intestine that is essential in the hydrolysis of carbohydrates to glucose. Because inhibiting this enzyme slows the release of glucose, α-Glucosidase inhibitors are appealing medications for treating diabetes as a carbohydrate-related illness. The present study includes the design, synthesis and antidiabetic potential of novel triazole based indole derivatives as α-glucosidase inhibitor. Among them, the compound R1 was found to be most potent with promising candidate with IC50 value of 10.1 µM and R2 and R3 showed the good inhibitory potency with IC50 values 12.95 µM, 11.35 µM, respectively when compared to the standard drug acarbose having IC50 value of 13.5 µM. In in vivo studies, body weight of the mice was increased when compared to standard drug acarbose, the blood glucose level of the mice was decreased, same as the total cholesterol level, LDL, and triglycerides level decreased in comparison to standard drug. The level HDL was increased as it is a good cholesterol in comparison to standard drug acarbose. Furthermore, these synthesized compounds were docked with α-glucosidase using PDB ID:3WY1 which showed that compound R1 having good docking score -6.734 kcal/mol and compound R2, R3 showed docking score -6.14, -6.10 kcal/mol, respectively when compared with standard acarbose having docking score -4.55 kcal/mol. R1 showed the similar interaction with amino acid PHE166, GLU271, comparison with standard drug Acarbose. The synthesized compounds have been confirmed for antidiabetic activity and may be used for further development of potent compounds.

Structural Insight on GPR119 Agonist as Potential Therapy for Type II Diabetes: A Comprehensive Review.

Diabetes Mellitus (DM) is a long-term metabolic condition that is characterized by excessive blood glucose. DM is the third most death-causing disease, leading to retinopathy, nephropathy, loss of vision, stroke, and cardiac arrest. Around 90% of the total cases of diabetic patients have Type II Diabetes Mellitus (T2DM). Among various approaches for the treatment of T2DM. G proteincoupled receptors (GPCRs) 119 have been identified as a new pharmacological target. GPR119 is distributed preferentially in the pancreas ß-cells and gastrointestinal tract (enteroendocrine cells) in humans. GPR119 receptor activation elevates the release of incretin hormones such as Glucagon-Like Peptide (GLP1) and Glucose Dependent Insulinotropic Polypeptide (GIP) from intestinal K and L cells. GPR119 receptor agonists stimulate intracellular cAMP production via Gαs coupling to adenylate cyclase. GPR119 has been linked to the control of insulin release by pancreatic ß-cells, as well as the generation of GLP-1 by enteroendocrine cells in the gut, as per in vitro assays. The dual role of the GPR119 receptor agonist in the treatment of T2DM leads to the development of a novel prospective anti-diabetic drug and is thought to have decreased the probability of inducing hypoglycemia. GPR119 receptor agonists exert their effects in one of two ways: either by promoting glucose absorption by ß-cells, or by inhibiting α-cells' ability to produce glucose. In this review, we summarized potential targets for the treatment of T2DM with special reference to GPR119 along with its pharmacological effects, several endogenous as well as exogenous agonists, and its pyrimidine nucleus containing synthetic ligands.

Recent updates on structural insights of MAO-B inhibitors: a review on target-based approach.

Parkinson's disease is a neurodegenerative disorder characterized by slow movement, tremors, and stiffness caused due to loss of dopaminergic neurons caused in the brain's substantia nigra. The concentration of dopamine is decreased in the brain. Parkinson's disease may be happened because of various genetic and environmental factors. Parkinson's disease is related to the irregular expression of the monoamine oxidase (MAO) enzyme, precisely type B, which causes the oxidative deamination of biogenic amines such as dopamine. MAO-B inhibitors, available currently in the market, carry various adverse effects such as dizziness, nausea, vomiting, lightheadedness, fainting, etc. So, there is an urgent need to develop new MAO-B inhibitors with minimum side effects. In this review, we have included recently studied compounds (2018 onwards). Agrawal et al. reported MAO-B inhibitors with IC50 0.0051 µM and showed good binding affinity. Enriquez et al. reported a compound with IC50 144 nM and bind with some critical amino acid residue Tyr60, Ile198, and Ile199. This article also describes the structure-activity relationship of the compounds and clinical trial studies of related derivatives. These compounds may be used as lead compounds to develop potent compounds as MAO-B inhibitors.

Field and atom-based 3D-QSAR models of chromone (1-benzopyran-4-one) derivatives as MAO inhibitors.

Monoamine oxidases (MAOs) are flavo-enzymes that aid in the oxidative deamination of neurotransmitters like dopamine, serotonin, and epinephrine. MAO inhibitors are antidepressants that work by preventing the breakdown of brain neurotransmitters and regulating mood. MAO inhibitors that use the chromone (1-benzopyran-4-one) structure have been found to be quite effective in studies. The current study involves the creation of pharmacophore models, 3-D QSAR, virtual screening, and docking investigations, all of which are evaluated using various criteria. The investigation included 39 ligands that emerged pharmacophore AHRRR_1, as the best pharmacophore model with a survival score of 5.6485. The 3D QSAR investigation revealed a significant model with the values of R2 = 0.9064 and Q2 = 0.8239. Docking study revealed that compound 18 had the highest docking (-10.402 kcal/mol) score in the series and showed interactions with the essential amino acid TYR398 required for MAO inhibitory activity. ZINC compounds were screened using the created pharmacophore model, which was followed up with a virtual screening study. The ZINC compounds with the best XP docking scores are ZINC03113255, ZINC07777127, ZINC05166353 and ZINC09341502 (with docking scores -10.021, -9.486, -8.031 and -7.792 kcal/mol, respectively). ZINC03113255, which showed the best score, has binding interactions with amino acid residues, TYR326, TYR398 and LYS296 of monoamine oxidase B. The ADME analysis demonstrated the compound's drug-like characteristics. The findings of this study may be used in the development of chromone compounds that target the MAO inhibitor.Communicated by Ramaswamy H. Sarma.

Recent Updates on Structural Aspects of ALK Inhibitors as an Anticancer Agent.

Presently, several protein kinases have been discovered with the aim to treat various cancers. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that plays a role in the pathogenesis of a wide variety of human cancers known as ALCLs, NSCLC, ovarian cancer, breast cancer, colorectal cancer, neuroblastoma, etc. The fulllength ALK receptor is a classical receptor tyrosine kinase composed of an amino-terminal extracellular domain and an intracellular tyrosine kinase domain. Crizotinib is a strong oral small-molecule first tyrosine kinase inhibitor of ALK to be used in the treatment of ALK-dependent NSCLC. Due to the drug resistance of first generation ALK inhibitors, researchers are trying to design and synthesize novel ALK inhibitors with various heterocyclic rings in which 2,4- diarylaminopyrimidine derivatives with a specific N-(3-pyridinylmethyl)urea moiety, 2-amino-4-(1-piperidine) pyridine derivatives, 7-azaindole and carboxamide derivatives and some others produced potential compounds. To overcome drug resistance, to get better affinity and to reduce drug toxicity, there is an urgent need for novel ALK inhibitors. The present review describes the ALK signaling, their inhibitors and related structure activity relationships for the development of potential ALK inhibitors.

Structural aspects of triazole derivatives as HSP90 inhibitors for the treatment of cancer: in silico studies.

HSP90, one important class of chaperons has been intensively investigated as a promising and novel class of drug target for cancer therapy from the past few decades. A series of 2-((4-resorcinolyl)-5-aryl-1, 2, 3-triazol-1-yl) acetate derivatives were taken in the present study for the generation of pharmacophore based models, predictive 3 D-QSAR models, docking and ZINC screening studies against HSP90. The investigation included 30 ligands which emerged DHRRR_1 having survival score of 5.59 was found the most effective pharmacophore model. The generated third PLS factor includes a model with significant Q2, R2, and R2 CV values as 0.62, 0.77, and 0.50, respectively. The molecular docking studies against HSP90 showed interactions with important amino acids such as GLY-97, ASN-106, THR-184, ASN-51, PHE-138 and SER-52 required for HSP90 inhibitory activity. According to the docking analysis compound 34 was the top scoring compound, had a docking score of -10.98 from the series and showed interactions with amino acids likeASP-93, GLY-97, AND ASP-102. Using pharmacophore characteristics, the virtual screening investigation was carried out and DHRRR_1 showed the potential ZINC compounds. The ZINC compounds ZINC72417069 and ZINC77522480 showed best XP docking scores (-8.205 and -7.103 consecutively) and the top-scoring compound ZINC72417069 displayed amino acid binding affinity with GLY-97, ASN-106, and THR-184 against HSP90, PDB ID: 2xjx. These ZINC compounds can be used as target for HSP90. The result of the study may further help to the scientist for the design and development of potential HSP90 inhibitors.

Recent Updates on Indole Derivatives as Kinase Inhibitors in the Treatment of Cancer.

Cancer is becoming a global threat as its treatment accounts for many challenges. Hence, newer inventions prioritize the requirement of developing novel anticancer agents. In this context, kinases have been exclusively investigated and developed as a promising and novel class of drug targets for anticancer regimen. Indole derivatives have been found to be most effective for targeting multiple kinases, such as PIM, CDK, TK, AKT, SRC, PI3K, PKD, GSK, etc., to inhibit cell proliferation for cancer. Recently, a group of researchers have proposed their research outcomes related to this moiety, such as Zhang et al. described some potent PI3K inhibitors by substitution at the 4th position of the indole ring. Kassis et al. enumerated several potent CDK5 inhibitors by substituting the 2nd and 6th positions of the indole ring. In the present review, we have taken the initiative to summarize structure-activity relationship (SAR) studies of indole derivatives as kinase inhibitors for the development of potential inhibitors.

Structural Perspective of Benzophenones Targeting Tubulin as Anticancer Agents.

Cancer is the leading cause of death and the most significant determinant of life expectancy in almost every country in this twenty-first century. According to the World Health Organization (WHO), cancer is responsible for the leading cause of death globally. Benzophenone derivatives are found in a variety of naturally occurring compounds which are known to be pharmacologically efficacious against a variety of diseases, including cancer. Microtubules are thought to be a good target for cancer chemotherapies. Microtubule polymerization and depolymerization are induced by a variety of natural, synthetic, and semisynthetic chemicals having a benzophenone nucleus, affecting tubulin dynamics. Several medications that affect microtubule dynamics are in various stages of clinical trials, including Combretastatins (phase II), Vincristine (clinically approved), Paclitaxel (in clinical usage), and epothilone (phase III), and only a few have been patented. Benzophenone derivatives target the colchicine binding site of microtubules, damage them and cause cell cycle arrest in the G2-M phase. Belonging to this class of molecules, phenstatin, a potent inhibitor of tubulin polymerization, has shown strongly inhibit cancer cell growth and arrest the G2/M phase of the cell cycle by targeting the colchicine binding site of microtubules. In the present manuscript, we described the benzophenone as tubulin polymerization inhibitors, their Structure-Activity Relationships (SARs) and molecular docking studies that reveal its binding affinity with the colchicine binding site.

An Investigative Review for Pharmaceutical Analysis of Fenofibrate.

HMG-CoA reductase inhibitors (statins), lipoprotein lipase activators (PPARα agonists) or fibrates are commonly used for controlling increased lipid levels in hyperlipidemia. Fenofibrate (FEN) belongs to the second generation prodrug fibric acid (isobutyric acid) derivative belonging to lipoprotein lipase activator class of drug. Results of clinical studies suggest that FEN can substantially reduce severe acute respiratory syndrome coronavirus 2. alpha and beta variant infection in human cell efficiently. This review article provides an in-depth examination of critical analytical methodologies used in the pharmaceutical analysis of FEN in pure forms, biological samples and pharmaceuticals. According to literature study reports several analytical techniques have been used for determination of FEN alone or in the combined dosage forms. Based on the literature, it was determined that high-performance liquid chromatography and UV/vis-spectrophotometry are the most widely used methods for FEN analysis. Sahoo et al. have developed the best HPLC method in bulk and pharmaceutical dosage form with the retention time of 19.268 min using phosphate buffer (pH 3.0): acetonitrile in the ratio of 30:70 (% v/v) as mobile phase. The information presented here may provide a solid foundation for future research on FEN in the field of drug analysis.

Recent Advances of PI3 Kinase Inhibitors: Structure Anticancer Activity Relationship Studies.

Phosphatidyl-inositol-3-kinase (PI3K) has emerged as a potential therapeutic target for the development of novel anticancer drugs. The dysregulation of PI3K has been associated with many human malignancies such as breast, colon, endometrial, brain, and prostate cancers. The PI3K kinases in their different isoforms namely α, ß, δ, and γ, encode PIK3CA, PIK3CB, PIK3CD, and PIK3CG genes. Specific gene mutation or overexpression of the protein is responsible for therapeutic failure of current therapeutics. Recently, various PI3K signaling pathway inhibitors have been identified which showed promising therapeutic results by acting on specific isoforms of the kinase too. Several inhibitors containing medicinally privileged scaffolds like oxadiazole, pyrrolotriazine, quinazoline, quinazolinone, quinazoline-chalcone hybrids, quinazoline-sulfonamide, pyrazolochalcone, quinolone hydroxamic acid, benzofuropyridinone, imidazopyridine, benzoxazines, dibenzoxanthene, indoloderivatives, benzimidazole, and benzothiazine derivatives have been developed to target PI3K pathway and/or a specific isoform. The PI3K inhibitors which are under clinical trial studies include GDC-0032, INK1117 for PI3K-α, and AZD8186 for PI3K-ß. This review primarily focuses on the structural insights and structure anticancer activity relationship studies of recent PI3K inhibitors including their clinical stages of development and therapeutic values.

Recent Progress in Histone Deacetylase (HDAC) 1 Inhibitors as Anticancer Agent.

Histone deacetylases (HDACs) are essential for maintaining homeostasis by catalyzing histone deacetylation. Aberrant expression of HDACs is associated with various human diseases. Although HDAC inhibitors are used as effective chemotherapeutic agents in clinical practice, their applications remain limited due to associated side effects induced by weak isoform selectivity. HDAC1 displays unique structure and cellular localization as well as diverse substrates and exhibits a wider range of biological functions than other isoforms. HDAC1 displays a unique structure primarily found in the nucleus and involved in epigenetic and transcriptional regulation. HDAC1 is ubiquitously expressed and associated with Sin3, NuRD, and CoRest transcription repressive complexes responsible for distinct cellular processes like cell proliferation and survival. HDAC1 inhibitors have been effectively used to treat various cancers such as gastric, breast, colorectal, prostate, colon, lung, ovarian, pancreatic, and inflammation without exerting significant toxic effects. In this review, we summarize four major structural classes of HDAC1 inhibitors (i.e., hydroxamic acid derivatives, benzamides, hydrazides, and thiols) with their structural activity relationship. This review is a comprehensive work on HDAC1 inhibitors to achieve deep insight of knowledge about the structural information of HDAC1 inhibitors. It may provide up-to-date direction for developing new selective HDAC1 inhibitors as anticancer agents.

Computational approaches for the design of novel dopamine D2 and serotonin 5-HT2A receptor dual antagonist towards schizophrenia.

Piperidine and piperazine derivatives exhibit a diverse range of biological applications, including antipsychotic activity. In this study, a dataset of molecules containing piperidine, piperazine moieties that possess serotonin 5-HT2A and dopamine D2 inhibitory activity have been chosen for Pharmacophore modeling, Quantitative Structure-Activity (3D-QSAR) Relationship, Molecular docking, and ADME studies. The pharmacophoric hypothesis was found to be AAHPRRR_1 having seven features as one H-bond acceptor (A), one hydrophobic (H), one positive ion acceptor (P), and three aromatic rings (R), with survival score = 6.465 and AUC = 0.92. Based on the best hypothesis, the ZINC-Data base was virtually screened to find out the lead molecules. 3D-QSAR model, including internal and external validation showed comparative molecular field analysis (CoMFA) against 5HT2A (q 2 = 0.552, R 2 = 0.889, and r 2 poured. = 0.653 and number of component 5) and comparative molecular similarity indices analysis (CoMSIA) (q 2 = 0.599, R 2 = 0.893, and r 2 pred. = 0.617), for D2 (CoMFA, q 2 = 0.577, R 2 = 0.863, and r 2 pred. = 0.598) (CoMSIA, q 2 = 0.532, R 2 = 0.82) all results exhibited better productivity and significant statistical reliability of the model. The docking study was carried out on the crystal structure of 5-HT2A having PDB ID; 6A93 and D2 receptor having PDB ID; 6CM4. The screened compound ZINC74289318 possess a higher docking score - 10.744 and - 11.388 than co-crystallized ligand docking score - 8.840 and - 10.06 against 5-HT2A and D2 receptor respectively. Further, ZINC74289318 was screened for all drug-likeness parameters and no showed violation of the Lipinski rule of five. Also, it was found to possess good bioavailability of 0.55 with synthetic accessibility of 4.42 which is greater than risperidone.