Recent advances in nanobiosensors for sustainable healthcare applications: A systematic literature review.

The need for novel healthcare treatments and drugs has increased due to the expanding human population, detection of newer diseases, and looming pandemics. The development of nanotechnology offers a platform for cutting-edge in vivo non-invasive monitoring and point-of-care-testing (POCT) for rehabilitative disease detection and management. The advancement and uses of nanobiosensors are currently becoming more common in a variety of scientific fields, such as environmental monitoring, food safety, biomedical, clinical, and sustainable healthcare sciences, since the advent of nanotechnology. The identification and detection of biological patterns connected to any type of disease (communicable or not) have been made possible in recent years by several sensing techniques utilizing nanotechnology concerning biosensors and nanobiosensors. In this work, 2218 articles are drawn and screened from six digital databases out of which 17 were shortlisted for this review by using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) technique. As a result, this study uses a systematic methodology to review some recently developed extremely sensitive nanobiosensors, along with their biomedical, point-of-care diagnostics (POCD), or healthcare applications and their capabilities, particularly for the prediction of some fatal diseases based on a few of the most recent publications. The potential of nanobiosensors for medicinal, therapeutic, or other sustainable healthcare applications, notably for ailments diagnostics, is also recognized as a way forward in the manifestation of future trends.

Recent advances in the development of active hybrid molecules in the treatment of cardiovascular diseases.

Multifactorial nature of the underlying pathophysiology of chronic disorders hinders in the effective treatment and management of many complex diseases. The conventional targeted therapies have limited applications due to highly complicated disease etiology. Cardiovascular diseases (CVDs) are the group of disorders of the heart and blood vessels. Currently, there is limited knowledge on the underlying cellular and molecular mechanisms of many of the CVDs due to their complex pathophysiology and co-morbidities. Their management with conventional medications results in failure due to adverse drug reactions and clinical specificity of solo-targeting drug therapy. Therefore, it is critical to introduce an alternative strategy to treat multi-factorial diseases. In the past few years, discovery and use of multi-targeted drug therapy with hybrid molecules have shown promising results with minimal side effects, and thus considered a most effective approach. In this review article, prominent hybrid molecules combining with different active moieties are reported to synergistically and simultaneously block different pathways involved in CVDs. Here, we provide a critical evaluation and discussion on their pharmacology with mechanistic insights and the structure activity relationship. The timely information provided in this article reveals the recent trends of molecular hybridization to the scientific community interested in CVDs and help them in designing the next generation of multi-targeting drug therapeutics.

LPS and oxLDL-induced S100A12 and RAGE expression in carotid arteries of atherosclerotic Yucatan microswine.

BACKGROUND: S100A12, also known as Calgranulin C, is a ligand for the receptor for advanced glycation end products (RAGE) and plays key roles in cardiovascular and other inflammatory diseases. Interactions between S100A12 and RAGE initiate downstream signaling activating extracellular signal-regulated kinases (ERK1/2), mitogen activated protein kinases (MAPK), and transcription factor NF-κB. This increases the expression of pro-inflammatory cytokines to induce the inflammatory response. S100A12, and RAGE play a critical role in the development and progression of atherosclerosis. There is a well-known relationship between the bacterial endotoxin lipopolysaccharide (LPS) and the lipid antigens oxidized low-density lipoprotein (oxLDL) in driving the immune response in atherosclerosis. METHODS AND RESULTS: Our study aimed to compare the potential of LPS and oxLDL in regulating the expression of S100A12 and RAGE in atherosclerosis. The expression of these proteins was assessed in the harvested carotid arteries from LPS- and oxLDL-treated atherosclerotic Yucatan microswine. Tissues were collected from five different treatment groups: (i) angioplasty alone, (ii) LPS alone, (iii) oxLDL alone, (iv) angioplasty with LPS, and (v) angioplasty with oxLDL. Immunohistochemical findings revealed that angioplasty with LPS induced higher expression of S100A12 and RAGE compared to other treatment groups. The results were further corroborated by testing their gene expression through qPCR in cultured vascular smooth muscle cells (VSMCs) isolated from control carotid arteries and LPS- and oxLDL-treated arteries. CONCLUSIONS: The results of this study suggest that LPS induces the expression of S100A12 and RAGE more than oxLDL in atherosclerotic artery and both S100A12 and RAGE could be therapeutic targets.

Design, Synthesis, biological investigations and molecular interactions of triazole linked tacrine glycoconjugates as Acetylcholinesterase inhibitors with reduced hepatotoxicity.

Tacrine is a known Acetylcholinesterase (AChE) inhibitors having hepatotoxicity as main liability associated with it. The present study aims to reduce its hepatotoxicity by synthesizing tacrine linked triazole glycoconjugates via Huisgen's [3 + 2] cycloaddition of anomeric azides and terminal acetylenes derived from tacrine. A series of triazole based glycoconjugates containing both acetylated (A-1 to A-7) and free sugar hydroxyl groups (A-8 to A-14) at the amino position of tacrine were synthesized in good yield taking aid from molecular docking studies and evaluated for their in vitro AChE inhibition activity as well as hepatotoxicity. All the hybrids were found to be non-toxic on HePG2 cell line at 200 µM (100 % cell viability) as compared to tacrine (35 % cell viability) after 24 h of incubation period. Enzyme kinetic studies carried out for one of the potent hybrids in the series A-1 (IC50 0.4 µM) revealed its mixed inhibition approach. Thus, compound A-1 can be used as principle template to further explore the mechanism of action of different targets involved in Alzheimer's disease (AD) which stands as an adequate chemical probe to be launched in an AD drug discovery program.

Design, synthesis, and biological evaluation of isatin-indole-3-carboxaldehyde hybrids as a new class of xanthine oxidase inhibitors.

A novel series of triazole-linked isatin-indole-3-carboxaldehyde hybrids based on the febuxostat skeleton and its binding site interactions were rationally designed and synthesized as potential xanthine oxidase inhibitors. Among the synthesized hybrids, A19 showed the most potent xanthine oxidase inhibition (IC50 = 0.37 µM) with the mixed-type inhibitory scenario. Structure-activity relationship studies revealed that methoxy (OCH3 ) substitution on position 5 of the isatin nucleus and a two-carbon distance between isatin and the triazole moiety is most tolerable for the inhibitory potential. Various binding interactions of A19 with the binding site of xanthine oxidase are also streamlined by molecular docking studies, which showcase the favorable binding pattern for xanthine oxidase inhibition by the hybrid. Furthermore, molecular dynamic studies were performed that suggest the stability of the enzyme-hybrid complex. Overall, the study suggests that hybrid A19 can act as an effective hit lead for further development of potent xanthine oxidase inhibitors.

Therapeutic potential of targeting the receptor for advanced glycation end products (RAGE) by small molecule inhibitors.

Receptor for advanced glycation end products (RAGE) is a 45 kDa transmembrane receptor of immunoglobulin family that can bind to various endogenous and exogenous ligands and initiate the inflammatory downstream signaling pathways. RAGE is involved in various disorders including cardiovascular and neurodegenerative diseases, cancer, and diabetes. This review summarizes the structural features of RAGE and its various isoforms along with their pathological effects. Mainly, the article emphasized on the translational significance of antagonizing the interactions of RAGE with its ligands using small molecules reported in the last 5 years and discusses future approaches that could be employed to block the interactions in the treatment of chronic inflammatory ailments. The RAGE inhibitors described in this article could prove as a powerful approach in the management of immune-inflammatory diseases. A critical review of the literature suggests that there is a dire need to dive deeper into the molecular mechanism of action to resolve critical issues that must be addressed to understand RAGE-targeting therapy and long-term blockade of RAGE in human diseases.

Targeting the Crosstalk of Immune Response and Vascular Smooth Muscle Cells Phenotype Switch for Arteriovenous Fistula Maturation.

Plaque formation, thrombosis, and embolism are the underlying causes of acute cardiovascular events such as myocardial infarction and stroke while early thrombosis and stenosis are common pathologies for the maturation failure of arteriovenous fistula (AVF). Chronic inflammation is a common underlying pathogenesis mediated by innate and adaptive immune response involving infiltration of immune cells and secretion of pro- and anti-inflammatory cytokines. Impaired immune cell infiltration and change in vascular smooth muscle cell (VSMC) phenotype play a crucial role in the underlying pathophysiology. However, the change in the phenotype of VSMCs in a microenvironment of immune cell infiltration and increased secretion of cytokines have not been investigated. Since change in VSMC phenotype regulates vessel remodeling after intimal injury, in this study, we investigated the effect of macrophages and pro-inflammatory cytokines, IL-6, IL-1ß, and TNF-α, on the change in VSMC phenotype under in vitro conditions. We also investigated the expression of the markers of VSMC phenotypes in arteries with atherosclerotic plaques and VSMCs isolated from control arteries. We found that the inhibition of cytokine downstream signaling may mitigate the effect of cytokines on the change in VSMCs phenotype. The results of this study support that regulating or targeting immune cell infiltration and function might be a therapeutic strategy to mitigate the effects of chronic inflammation to attenuate plaque formation, early thrombosis, and stenosis, and thus enhance AVF maturation.

Therapeutic Potential of Targeting the HMGB1/RAGE Axis in Inflammatory Diseases.

High mobility group box 1 (HMGB1) is a nuclear protein that can interact with a receptor for advanced glycation end-products (RAGE; a multi-ligand immunoglobulin receptor) and mediates the inflammatory pathways that lead to various pathological conditions, such as cancer, diabetes, neurodegenerative disorders, and cardiovascular diseases. Blocking the HMGB1/RAGE axis could be an effective therapeutic approach to treat these inflammatory conditions, which has been successfully employed by various research groups recently. In this article, we critically review the structural insights and functional mechanism of HMGB1 and RAGE to mediate inflammatory processes. More importantly, current perspectives of recent therapeutic approaches utilized to inhibit the communication between HMGB1 and RAGE using small molecules are also summarized along with their clinical progression to treat various inflammatory disorders. Encouraging results are reported by investigators focusing on HMGB1/RAGE signaling leading to the identification of compounds that could be useful in further clinical studies. We highlight the current gaps in our knowledge and future directions for the therapeutic potential of targeting key molecules in HMGB1/RAGE signaling in the pathophysiology of inflammatory diseases.

Rational approaches for the design of various GABA modulators and their clinical progression.

GABA (γ-amino butyric acid) is an important inhibitory neurotransmitter in the central nervous system. Attenuation of GABAergic neurotransmission plays an important role in the etiology of several neurological disorders including epilepsy, Alzheimer's disease, Huntington's chorea, migraine, Parkinson's disease, neuropathic pain, and depression. Increase in the GABAergic activity may be achieved through direct agonism at the GABAA receptors, inhibition of enzymatic breakdown of GABA, or by inhibition of the GABA transport proteins (GATs). These functionalities make GABA receptor modulators and GATs attractive drug targets in brain disorders associated with decreased GABA activity. There have been several reports of development of GABA modulators (GABA receptors, GABA transporters, and GABAergic enzyme inhibitors) in the past decade. Therefore, the focus of the present review is to provide an overview on various design strategies and synthetic approaches toward developing GABA modulators. Furthermore, mechanistic insights, structure-activity relationships, and molecular modeling inputs for the biologically active derivatives have also been discussed. Summary of the advances made over the past few years in the clinical translation and development of GABA receptor modulators is also provided. This compilation will be of great interest to the researchers working in the field of neuroscience. From the light of detailed literature, it can be concluded that numerous molecules have displayed significant results and their promising potential, clearly placing them ahead as potential future drug candidates.

Most recent strategies targeting estrogen receptor alpha for the treatment of breast cancer.

Breast cancer is the most prominent, frequently diagnosed and leading cause of death among women. Estrogen is an agonist of estrogen receptor alpha (ER-α), expressed in mammary glands and is responsible for initiating many signalling pathways that lead to differentiation and development of breast tissue. Any mutations in these signalling pathways result in irregular growth of mammary tissue, leading to the development of tumour or cancer. All these observations attract the attention of researchers to antagonize ER-α receptor either by developing selective estrogen receptor modulators or by selective estrogen receptor degraders. Therefore, this article provides a brief overview of various factors that are responsible for provoking breast cancer in women and design strategies recently used by the various research groups across the world for antagonizing or demodulating ER-α.

New coumarin-benzotriazole based hybrid molecules as inhibitors of acetylcholinesterase and amyloid aggregation.

A novel series of triazole tethered coumarin-benzotriazole hybrids based on donepezil skeleton has been designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD). Among the synthesized compounds 13b showed most potent acetylcholinesterase (AChE) inhibition (IC50 = 0.059 µΜ) with mixed type inhibition scenario. Structure-activity relationship revealed that three-carbon alkyl chain connecting coumarin and triazole is well tolerable for inhibitory potential. Hybrids obtained from 4-hydroxycoumarin and 1-benzotriazole were most potent AChE inhibitors. The inhibitory potential of all compounds against butyrylcholinesterase was also evaluated but all showed negligible activity suggesting that the hybrid molecules are selective AChE inhibitors. 13b (most potent AChE inhibitor) also showed copper-induced Aß1-42 aggregation inhibition (34.26% at 50 µΜ) and chelating properties for metal ions (Cu2+, Fe2+, and Zn2+) involved in AD pathogenesis along with DNA protective potential against degenerative actions of OH radicals. Molecular modelling studies confirm the potential of 13b in blocking both PAS and CAS of AChE. In addition, interactions of 13b with Aß1-42 monomer are also streamlined. Therefore, hybrid 13b can act as an effective hit lead molecule for further development of selective AChE inhibitors as multifunctional anti-Alzheimer's agents.

Rational approaches, design strategies, structure activity relationship and mechanistic insights for therapeutic coumarin hybrids.

Hybrid molecules, furnished by combining two or more pharmacophores is an emerging concept in the field of medicinal chemistry and drug discovery that has attracted substantial traction in the past few years. Naturally occurring scaffolds such as coumarins display a wide spectrum of pharmacological activities including anticancer, antibiotic, antidiabetic and others, by acting on multiple targets. In this view, various coumarin-based hybrids possessing diverse medicinal attributes were synthesized in the last five years by conjugating coumarin moiety with other therapeutic pharmacophores. The current review summarizes the recent development (2014 and onwards) of these pharmacologically active coumarin hybrids and demonstrates rationale behind their design, structure-activity relationships (SAR) and mechanistic studies performed on these hybrid molecules. This review will be beneficial for medicinal chemist and chemical biologist, and in general to the drug discovery community and will facilitate the synthesis and development of novel, potent coumarin hybrid molecules serving as lead molecules for the treatment of complex disorders.

Triazole tethered isatin-coumarin based molecular hybrids as novel antitubulin agents: Design, synthesis, biological investigation and docking studies.

In an attempt to develop potent anti-tubulin agents against most dreadful disease cancer, a library of 28 novel triazole tethered isatin-coumarin hybrids were synthesized by click chemistry approach. Synthesized hybrids were characterized and evaluated against a panel of human cancer cell lines viz. THP-1, COLO-205, HCT-116 and PC-3. Biological assay unveiled that, compounds A-1 to A-6, B-1 to B-4 and C-1 to C-3 displayed significant inhibitory potential against THP-1, COLO-205 and HCT-116 cell lines which were more sensitive towards the designed hybrids. PC-3 among these cell lines was found to be almost resistant. Established SAR revealed marked dependence of the cytotoxic activity on the type of substituent on isatin and the length of carbon-bridge connecting isatin moiety with triazole ring. Unsubstituted isatin and two carbon-bridge were found to be crucial for cytotoxicity. Three most potent hybrids (A-1, A-2 and B-1) were further tested for tubulin polymerization inhibition. Among these three compounds, A-1 found to be endowed with most prominent tubulin polymerization inhibition potential with IC50 value of 1.06µM which was further confirmed by using confocal microscopy. Possible binding interactions between the most potent hybrid molecule A-1 and tubulin were also divulged by molecular modeling studies.

Benzoflavones as cholesterol esterase inhibitors: Synthesis, biological evaluation and docking studies.

A library of forty 7,8-benzoflavone derivatives was synthesized and evaluated for their inhibitory potential against cholesterol esterase (CEase). Among all the synthesized compounds seven benzoflavone derivatives (A-7, A-8, A-10, A-11, A-12, A-13, A-15) exhibited significant inhibition against CEase in in vitro enzymatic assay. Compound A-12 showed the most promising activity with IC50 value of 0.78nM against cholesterol esterase. Enzyme kinetic studies carried out for A-12, revealed its mixed-type inhibition approach. Molecular protein-ligand docking studies were also performed to figure out the key binding interactions of A-12 with the amino acid residues of the enzyme's active site. The A-12 fits well at the catalytic site and is stabilized by hydrophobic interactions. It completely blocks the catalytic assembly of CEase and prevents it to participate in ester hydrolysis mechanism. The favorable binding conformation of A-12 suggests its prevailing role as CEase inhibitor.

A prospective, randomized comparison of shock wave lithotripsy, retrograde intrarenal surgery and miniperc for treatment of 1 to 2 cm radiolucent lower calyceal renal calculi: a single center experience.

PURPOSE: A prospective, randomized comparison of shock wave lithotripsy, retrograde intrarenal surgery and miniperc for the treatment of 1 to 2 cm radiolucent lower calyceal renal calculi was done to evaluate the safety and efficacy of these procedures. MATERIALS AND METHODS: Patients with a single 1 to 2 cm radiolucent lower calyceal renal stone who underwent treatment between January 2012 and May 2013 were included in study. They were randomized to shock wave lithotripsy, retrograde intrarenal surgery and miniperc groups. Patient demographic profiles, success and re-treatment rates, auxiliary procedures and complications were analyzed. RESULTS: A total of 45 patients were enrolled in each of the shock wave lithotripsy, retrograde intrarenal surgery and miniperc groups. Three, 2 and 4 patients, respectively, were excluded from final analysis due to a matrix stone diagnosis. Mean procedure and fluoroscopy times were significantly greater in the miniperc group than in the other groups. Hospital stay (3.1 days vs 3.1 hours and 1.3 days, p = 0.01) and the blood transfusion rate (13.3% vs 0% and 0%, p = 0.03) were significantly higher for miniperc vs shock wave lithotripsy and retrograde intrarenal surgery, respectively. The re-treatment rate (63.4% vs 2.1% and 2.2%, p <0.001) and the auxiliary procedure rate (20.2% vs 8.8% and 6.6%, p = 0.02) were significantly greater for shock wave lithotripsy than for retrograde intrarenal surgery and miniperc, respectively. The 3-month stone-free rate of shock wave lithotripsy, retrograde intrarenal surgery and miniperc was 73.8% (31 of 42 patients), 86.1% (37 of 43) and 95.1% (39 of 41), respectively (p = 0.01). CONCLUSIONS: Miniperc and retrograde intrarenal surgery were more effective than shock wave lithotripsy to treat 1 to 2 cm radiolucent lower calyceal renal calculi in terms of a better stone-free rate, and lesser auxiliary and re-treatment rates. However, miniperc resulted in more complications, greater operative time and radiation exposure, and a longer hospital stay.

Dorsal versus ventral onlay buccal mucosal graft urethroplasty for long-segment bulbar urethral stricture: A prospective randomized study.

OBJECTIVES: To compare safety and efficacy of ventral versus dorsal onlay buccal mucosal graft urethroplasty in patients with long-segment incomplete bulbar urethral stricture. METHODS: This was a single center, prospective, randomized trial. Patients with long-segment (>2 cm) incomplete bulbar urethral stricture and meeting eligibility criteria were enrolled in the study. They were randomized into two study groups: group A undergoing dorsal onlay buccal mucosal graft urethroplasty and group B undergoing ventral onlay buccal mucosal graft urethroplasty. The two groups were compared statistically with regard to International Prostate Symptom Score, maximum flow rate, intraoperative parameters and complications. RESULTS: A total of 80 eligible patients were randomized into two equal groups of 40 patients each. The preoperative International Prostate Symptom Score, maximum flow rate and intraoperative parameters were not significantly different between the two groups. At 12-month follow up, the mean International Prostate Symptom Score showed 324.95% and 353.59% improvement, whereas the mean maximum flow rate showed 208.43% and 201.93% improvement in group A and B, respectively. There was no significant difference between International Prostate Symptom Score and maximum flow rate data between the two groups at 3- and 12-month follow up. The success rate of surgery was similar between group A and B (92.5% vs 90%) with no significant difference noted between them. CONCLUSION: Dorsal and ventral onlay buccal mucosal graft urethroplasty have comparable efficacy and complication rates for treatment of long-segment incomplete bulbar urethral strictures.

Safety of 12 core transrectal ultrasound guided prostate biopsy in patients on aspirin.

OBJECTIVE: To prospectively assess safety outcome of TRUS guided prostate biopsy in patients taking low dose aspirin. MATERIALS AND METHODS: Consecutive patients, who were planned for 12 core TRUS guided prostate biopsy and satisfied eligibility criteria, were included in the study and divided into two Groups: Group A: patients on aspirin during biopsy, Group B: patients not on aspirin during biopsy, including patients in whom aspirin was stopped prior to the biopsy. Parameters included for statistical analysis were: age, serum prostate specific antigen (PSA), prostate volume, hemoglobin (Hb %), number of hematuria episodes, number of patient reporting hematuria, hematuria requiring intervention, number of patient reporting hematospermia and number of patient reporting rectal bleeding. RESULTS: Of 681 eligible patients, Group A and B had 191 and 490 patients respectively. The mean age, prostate volume, serum PSA and pre-biopsy hemoglobin were similar in both Groups with no significant differences noted between them. None of the post-biopsy complications, including number of hematuria episodes (p=0.83), number of patients reporting hematuria (p=0.55), number of patients reporting hematospermia (p=0.36) and number of patients reporting rectal bleeding (p=0.65), were significantly different between Groups A and B respectively. None of the hemorrhagic complication in either group required intervention and were self limiting. CONCLUSION: Continuing low dose aspirin during TRUS guided prostate biopsy neither alters the minor bleeding episodes nor causes major bleeding complication. So, discontinuation of low dose aspirin prior to TRUS guided prostate biopsy is not required.

Synthesis and evaluation of naphthoflavones as a new class of non purine xanthine oxidase inhibitors.

In view of reported xanthine oxidase inhibitory potential of naphthopyrans and flavones, naphthoflavones as hybrids of the two were designed, synthesized and evaluated for in vitro xanthine oxidase inhibitory activity in the present study. The results of the assay revealed that the naphthoflavones possess promising inhibitory potential against the enzyme with IC50 values ranging from 0.62 to 41.2 µM. Structure activity relationship indicated that the nature and placement of substituents on the phenyl ring at 2nd position remarkably influences the inhibitory activity. Substitution of halo and nitro groups at ortho and para position of the phenyl ring (2nd position) remarkably favored the activity. NF-4 with p-fluoro phenyl ring was the most potent inhibitor with IC50 value of 0.62 µM. Enzyme kinetics study was also performed to investigate the inhibition mechanism and it was found that the naphthoflavones displayed mixed type inhibition. The basis of significant inhibition of xanthine oxidase by NF-4 was rationalized by molecular modeling studies.

A novel approach for detail-enhanced exposure fusion using guided filter.

In this paper we propose a novel detail-enhancing exposure fusion approach using nonlinear translation-variant filter (NTF). With the captured Standard Dynamic Range (SDR) images under different exposure settings, first the fine details are extracted based on guided filter. Next, the base layers (i.e., images obtained from NTF) across all input images are fused using multiresolution pyramid. Exposure, contrast, and saturation measures are considered to generate a mask that guides the fusion process of the base layers. Finally, the fused base layer is combined with the extracted fine details to obtain detail-enhanced fused image. The goal is to preserve details in both very dark and extremely bright regions without High Dynamic Range Image (HDRI) representation and tone mapping step. Moreover, we have demonstrated that the proposed method is also suitable for the multifocus image fusion without introducing artifacts.

Discovery of Potential RAGE inhibitors using Receptor-Based Pharmacophore Modeling, High Throughput Virtual Screening and Docking Studies.

Receptor for Advanced Glycation End products (RAGE) is a transmembrane receptor that can bind to various endogenous and exogenous ligands and initiate the inflammatory downstream signaling pathways. So far RAGE has been involved in various disorders including cardiovascular and neurodegenerative diseases, cancer, and diabetes. Blocking the interactions between RAGE and its ligands is a therapeutic approach to treat these conditions. In this context, we effectively utilized the receptor-based-pharmacophore modeling to discover structurally diverse molecular compounds having potential to effectively bind with RAGE. Two pharmacophore models were developed on V-domain of RAGE using Phase application of Schrodinger suite. The developed pharmacophoric features were used for screening of 1.8 million drug-like molecules downloaded from ChEMBL database. The molecules were scrutinized according to their molecular weight as well as clogP values. Phase screening was performed to find out the molecules that matched the developed pharmacophoric features that were further selected to analyze their binding modes using high-throughput virtual screening, extra precision docking studies and MM-GBSA ΔG binding calculations. These analyses provided ten hit RAGE inhibitory molecules that can bind to two different shallow binding sites on the V-domain of RAGE. Among the obtained compounds two compounds ChEMBL501494 and ChEMBL4081874 were found with best binding free energies that proved their receptor-ligand complex stability within their respective binding cavity on RAGE. Therefore, these molecules could be utilized for further designing and optimizing the future class of potential RAGE inhibitors.