Exploring marine-derived bioactive compounds for dual inhibition of Pseudomonas aeruginosa LpxA and LpxD: integrated bioinformatics and cheminformatics approaches.

Pseudomonas aeruginosa can cause serious nosocomial infections. Targeting the biosynthesis of Lipid A, a major structural domain of lipopolysaccharide (LPS) in P. aeruginosa has emerged as a valuable strategy for developing novel therapeutic agents. The biosynthesis of Lipid A involves the activation of homolog enzymes including LpxA and LpxD. LpxA enzyme facilitates the transfer of R-3-hydroxydecanoic fatty acid to uridine diphosphate N-acetylglucosamine in the first step. While LPxD is accountable in third step, wherein R-3-hydroxydodecanoate is transferred to the 2' amine of UDP-3-O-(3-hydroxydecanoyl) utilizing an ACP donor. The exploration of LpxA and LpxD has been largely neglected, as no specific small-molecule inhibitors have been identified, thus far, except for peptide inhibitors. Here, we report the identification of potential dual inhibitors of the lipid A biosynthesis pathway that target both the LpxA and LpxD enzymes as novel antibiotic agents. Among the virtually screened 32,000 marine bioactive compounds Oscillatoxin A, NCI60_041046, and LTS0192263 exhibited optimal docking interactions with LpxA and LpxD, respectively. MD simulation and MMPBSA data showcased stable interactions between selected marine products and LpxA/LpxD. FMO analysis showed that Oscillatoxin A and NCI60_041046 are the most chemically active molecules. MEP analysis data highlighted the possible electrophilic and nucleophilic distribution zones present in the structure. In addition, these bioactive molecules showed acceptable ADMET profiles. These data confirmed that Oscillatoxin A, NCI60_041046, and LTS0192263 could serve as seeds for the development of potential therapeutics to combat P. aeruginosa infection.

Flavonoids as potential KRAS inhibitors: DFT, molecular docking, molecular dynamics simulation and ADMET analyses.

KRAS mutations linked with cancer. Flavonoids were docked against KRAS G12C and G12D receptors. Abyssinone III, alpha naphthoflavone, beta naphthoflavone, abyssinone I, abyssinone II and beta naphthoflavone, genistin, daidzin showed good docking scores against KRAS G12C and G12D receptors, respectively. The MD simulation data revealed that Rg, RMSD, RMSF, and SASA values were within acceptable limits. Alpha and beta naphthoflavone showed good binding energies with KRAS G12C and G12D receptors. DFT and MEP analysis highlighted the nucleophilic and electrophilic zones of best-docked flavonoids. A novel avenue for the control of KRAS G12C and G12D mutations is made possible by flavonoids.

In the present study, we computationally established the role of flavonoids as KRAS G12C and G12D inhibitors.Initially we selected 93 flavonoids and docked against 8AFB (KRAS G12C) and 7RT1 (KRAS G12D) using Sotorasib and MRTX 1133 as standards.A 100 ns MD simulation revealed that the radius of gyration, RMSD, RMSF, and SASA values were within acceptable limits and that there were a greater number of donors and acceptors for hydrogen bonds.In addition to the KRAS G12C 8AFB receptor, the maximum binding energy was shown by alpha Naphthoflavone (−26.471 kJ/mol), and for the KRAS G12D 7RT1 receptor, the maximum binding energy was shown by beta Naphthoflavone (−15.433 kJ/mol).FMO and MEP analysis data highlighted the best-docked flavonoids' potential areas for nucleophilic and electrophilic attacks.ADMET properties have been calculated and provide safe use and low toxicity for both aquatic and non-aquatic species.

Exploring Cinnamoyl-Substituted Mannopyranosides: Synthesis, Evaluation of Antimicrobial Properties, and Molecular Docking Studies Targeting H5N1 Influenza A Virus.

The pursuit of innovative combinations for the development of novel antimicrobial and antiviral medications has garnered worldwide interest among scientists in recent times. Monosaccharides and their glycosides, such as methyl α-d-mannopyranoside derivatives, play a significant role in the potential treatment of viral respiratory pathologies. This study was undertaken to investigate and assess the synthesis and spectral characterization of methyl α-d-mannopyranoside derivatives 2-6, incorporating various aliphatic and aromatic groups. The investigation encompassed comprehensive in vitro antimicrobial screening, examination of physicochemical properties, molecular docking analysis, molecular dynamics simulations, and pharmacokinetic predictions. A unimolar one-step cinnamoylation reaction was employed under controlled conditions to produce methyl 6-O-cinnamoyl-α-d-mannopyranoside 2, demonstrating selectivity at the C-6 position. This represented a pivotal step in the development of potential antimicrobial derivatives based on methyl α-d-mannopyranoside. Subsequently, four additional methyl 6-O-cinnamoyl-α-d-mannopyranoside derivatives were synthesized with reasonably high yields. The chemical structures of these novel analogs were confirmed through a thorough analysis of their physicochemical properties, elemental composition, and spectroscopic data. In vitro antimicrobial assays were conducted against six bacterial strains and two fungal strains, revealing promising antifungal properties of these methyl α-d-mannopyranoside derivatives in comparison to their antibacterial activity. Moreover, cytotoxicity testing revealed that the compounds are less toxic. Further supporting these findings, molecular docking studies were performed against the H5N1 influenza A virus, indicating significant binding affinities and nonbonding interactions with the target protein 6VMZ. Notably, compounds 4 (-7.2) and 6 (-7.0) exhibited the highest binding affinities. Additionally, a 100 ns molecular dynamics simulation was conducted to assess the stability of the complex formed between the receptor 6VMZ and methyl α-d-mannopyranoside derivatives under in silico physiological conditions. The results revealed a stable conformation and binding pattern within the stimulating environment. In silico pharmacokinetic and toxicity assessments of the synthesized molecules were performed using Osiris software (version 2.9.1). Compounds 4 and 6 demonstrated favorable computational and pharmacological activities, albeit with a low drug score, possibly attributed to their higher molecular weight and irritancy. In conclusion, this study showcases the synthesis and evaluation of methyl α-d-mannopyranoside derivatives as promising candidates for antimicrobial and antifungal agents. Molecular docking and dynamics simulations, along with pharmacological predictions, contribute to our understanding of their potential therapeutic utility, although further research may be warranted to address certain pharmacological aspects.

In Silico Pharmacokinetics, Molecular Docking and Molecular Dynamics Simulation Studies of Nucleoside Analogs for Drug Discovery- A Mini Review.

Nucleoside analogs have been widely used as antiviral, antitumor, and antiparasitic agents due to their ability to inhibit nucleic acid synthesis. Adenosine, cytidine, guanosine, thymidine and uridine analogs such as didanosine, vidarabine, remdesivir, gemcitabine, lamivudine, acyclovir, abacavir, zidovusine, stavudine, and idoxuridine showed remarkable anticancer and antiviral activities. In our previously published articles, our main intention was to develop newer generation nucleoside analogs with acylation-induced modification of the hydroxyl group and showcase their biological potencies. In the process of developing nucleoside analogs, in silico studies play an important role and provide a scientific background for biological data. Molecular interactions between drugs and receptors followed by assessment of their stability in physiological environments, help to optimize the drug development process and minimize the burden of unwanted synthesis. Computational approaches, such as DFT, FMO, MEP, ADMET prediction, PASS prediction, POM analysis, molecular docking, and molecular dynamics simulation, are the most popular tools to culminate all preclinical study data and deliver a molecule with maximum bioactivity and minimum toxicity. Although clinical drug trials are crucial for providing dosage recommendations, they can only indirectly provide mechanistic information through researchers for pathological, physiological, and pharmacological determinants. As a result, in silico approaches are increasingly used in drug discovery and development to provide mechanistic information of clinical value. This article portrays the current status of these methods and highlights some remarkable contributions to the development of nucleoside analogs with optimized bioactivity.

Macromolecules: Synthesis, antimicrobial, POM analysis and computational approaches of some glucoside derivatives bearing acyl moieties.

Macromolecules i.e., carbohydrate derivatives are crucial to biochemical and medical research. Herein, we designed and synthesized eight methyl α-D-glucopyranoside (MGP) derivatives (2-8) in good yields following the regioselective direct acylation method. The structural configurations of the synthesized MGP derivatives were analyzed and verified using multiple physicochemical and spectroscopic techniques. Antimicrobial experiments revealed that almost all derivatives demonstrated noticeable antifungal and antibacterial efficacy. The synthesized derivatives showed minimum inhibitory concentration (MIC) values ranging from 0.75 µg/mL to 1.50 µg/mL and minimum bactericidal concentrations (MBCs) ranging from 8.00 µg/mL to 16.00 µg/mL. Compound 6 inhibited Ehrlich ascites carcinoma (EAC) cell proliferation by 10.36% with an IC50 of 2602.23 µg/mL in the MTT colorimetric assay. The obtained results were further rationalized by docking analysis of the synthesized derivatives against 4URO and 4XE3 receptors to explore the binding affinities and nonbonding interactions of MGP derivatives with target proteins. Compound 6 demonstrated the potential to bind with the target with the highest binding energy. In a stimulating environment, a molecular dynamics study showed that MGP derivatives have a stable conformation and binding pattern. The MGP derivatives were examined using POM (Petra/Osiris/Molinspiration) bioinformatics, and as a result, these derivatives showed good toxicity, bioavailability, and pharmacokinetics. Various antifungal/antiviral pharmacophore (Oδ-, O'δ-) sites were identified by using POM investigations, and compound 6 was further tested against other pathogenic fungi and viruses, such as Micron and Delta mutants of SARS-CoV-2.

Computational Studies and Antimicrobial Activity of 1-(benzo[d]oxazol-2-yl)-3,5-Diphenylformazan Derivatives.

BACKGROUND: Due to the biological importance of the benzoxazole derivatives, some 1-(benzo[d]oxazol-2-yl)-3,5-diphenyl-formazans (4a-f) were synthesized and screened for in-silico studies and in-vitro antibacterial activity. METHODS: The benzo[d]oxazole-2-thiol (1) was prepared by reacting with 2-aminophenol and carbon disulfide in the presence of alcoholic potassium hydroxide. Then 2-hydrazinylbenzo[d]oxazole (2) was synthesized from the reaction of compound 1 with hydrazine hydrate in the presence of alcohol. Compound 2 was reacted with aromatic aldehydes to give Schiff base, 2-(2-benzylidene-hydrazinyl)benzo[d]oxazole derivatives (3a-f). The title compounds, formazan derivatives (4a-f), were prepared by a reaction of benzene diazonium chloride. All compounds were confirmed by their physical data, FTIR, 1H-NMR, and 13CNMR spectral data. All the prepared title compounds were screened for in-silico studies and in-vitro antibacterial activity on various microbial strains. RESULTS: Molecular docking against the 4URO receptor demonstrated that molecule 4c showed a maximum dock score of (-) 8.0 kcal/mol. MD simulation data reflected the stable ligand-receptor interaction. As per MM/PBSA analysis, the maximum free binding energy of (-) 58.831 kJ/mol was exhibited by 4c. DFT calculation data confirmed that most of the molecules were soft molecules with electrophilic nature. CONCLUSION: The synthesized molecules were validated using molecular docking, MD simulation, MMPBSA analysis, and DFT calculation. Among all the molecules, 4c showed maximum activity. The activity profile of the synthesized molecules against tested micro-organisms was found to be 4c>4b>4a>4e>4f>4d.

Establishing the Role of Iridoids as Potential Kirsten Rat Sarcoma Viral Oncogene Homolog G12C Inhibitors Using Molecular Docking; Molecular Docking Simulation; Molecular Mechanics Poisson-Boltzmann Surface Area; Frontier Molecular Orbital Theory; Molecular Electrostatic Potential; and Absorption, Distribution, Metabolism, Excretion, and Toxicity Analysis.

The RAS gene family is one of the most frequently mutated oncogenes in human cancers. In KRAS, mutations of G12D and G12C are common. Here, 52 iridoids were selected and docked against 8AFB (KRAS G12C receptor) using Sotorasib as the standard. As per the docking interaction data, 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester (dock score: -9.9 kcal/mol), 6'-O-trans-para-coumaroyl geniposidic acid (dock score: -9.6 kcal/mol), 6-O-trans-cinnamoyl-secologanoside (dock score: -9.5 kcal/mol), Loganic acid 6'-O-beta-d-glucoside (dock score: -9.5 kcal/mol), 10-O-succinoylgeniposide (dock score: -9.4), Loganic acid (dock score: -9.4 kcal/mol), and Amphicoside (dock score: -9.2 kcal/mol) showed higher dock scores than standard Sotorasib (dock score: -9.1 kcal/mol). These common amino acid residues between iridoids and complexed ligands confirmed that all the iridoids perfectly docked within the receptor's active site. The 100 ns MD simulation data showed that RMSD, RMSF, radius of gyration, and SASA values were within range, with greater numbers of hydrogen bond donors and acceptors. MM/PBSA analysis showed maximum binding energy values of -7309 kJ/mol for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester. FMO analysis showed that 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester was the most likely chemically reactive molecule. MEP analysis data highlighted the possible electrophilic and nucleophilic attack regions of the best-docked iridoids. Of all the best-docked iridoids, Loganic acid passed Lipinski, Pfizer, and GSK filters with a similar toxicity profile to Sotorasib. Thus, if we consider these iridoids to be KRAS G12C inhibitors, they will be a boon to mankind.

Combination Therapy of Ledipasvir and Itraconazole in the Treatment of COVID-19 Patients Coinfected with Black Fungus: An In Silico Statement.

The manuscript mainly aimed at providing clues on improving the innate immunity of coronavirus patients and safeguarding them from both new mutant strains and black fungus infections. Coronavirus is readily mutating from one variant to another. Among the several variants, we selected SARS-CoV-2 B.1.1.7 in this study. Upon infection of any virus, ideally, the phagocytic cells of the host engulf and destroy the virus by a mechanism called phagocytosis. However, compromised immunity impairs phagocytosis, and thus, restoring the immune system is crucial for a speedy recovery of infected patients. The autophagy and activation of Toll-like receptor-4 are the only ways to restore innate immunity. Recently, immunocompromised COVID-19 patients have been suffering from the coinfection of black fungus. Rhizomucor, a black fungus species, causes more than 75% of cases of mucormycosis. Here, we present the results of molecular docking studies of sixty approved antiviral drugs targeting receptors associated with the SARS-CoV-2 B 1.1.7 variant (PDB id: 7NEH), activating the innate immune system (PDB id: 5YEC and 5IJC). We also studied the twenty approved antifungal drugs with Rhizomucor miehei lipase propeptide (PDB id: 6QPR) to identify the possible combination therapy for patients coinfected with coronavirus and black fungus. The ledipasvir showed excellent docking interactions with the 7NEH, 5YEC, and 5IJC, indicating that it is a perfect candidate for the treatment of COVID-19 patients. Itraconazole showed significant interaction with 6QPR of Rhizomucor miehei, suggesting that itraconazole can treat black fungus infections. In conclusion, the combination therapy of ledipasvir and itraconazole can be a better alternative for treating COVID-19 patients coinfected with black fungus.

Indazole-based microtubule-targeting agents as potential candidates for anticancer drugs discovery.

Tremendous research is focused on developing novel drug candidates targeting microtubules to inhibit their function in several cellular processes, including cell division. In this regard, several indazole derivatives were sought to target the colchicine binding site on the ß-tubulin, a crucial protein required to form microtubules, to develop microtubule targeting agents. Even though there are several reviews on the indazole-based compounds, none of them focused on using indazole scaffold to develop microtubule targeting agents. Therefore, this review aims to present the advances in research on compounds containing indazole scaffolds as microtubule targeting agents based on the articles published in the last two decades. Among the articles reviewed, we found that compounds 6 and 7 showed the lowest IC50 values of 0.6 âˆ¼ 0.9 nM in the cell line studies, making them the strongest indazole derivatives that target microtubules. The compounds 30, 31, 37 (IC50 = ∼ 1 nM) and compounds 8, 38 (IC50 = ∼ 2 nM) have proved to be potent microtubule inhibitors. The compounds 18, 31, 44, 45 also showed strong anticancer activity (IC50 = ∼ 8 nM). It is important to notice that except for compounds 9, 12, 13, 15, and SRF, the top activity compounds including 6, 7, 8, 10, 11, 30, 31, 37, 44, and 45 contain 3,4,5­trimethoxyphenyl substitution similar to that of colchicine. Therefore, it appears that the 3,4,5­trimethoxyphenyl substituent on the indazole scaffold is crucial for targeting CBS.

Indazole Derivatives Effective against Gastrointestinal Diseases.

BACKGROUND: In this fast-growing lifestyle, humans are in the race against time to cope up with busy schedule. Less exercise, consumption of high calorie-low fiber food and stress take us one step closer towards digestive dysfunction. Dysfunctional digestive system causes various gastrointestinal disorders like constipation, IBS, UC, diarrhea, gastrointestinal tract immobility, hyperglycemia, hemorrhoids, fistula, anal fissures, stomach cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer and metabolic syndrome. Amongst various natural and synthetic indazole derivatives nigellicine, nigellamine, nigellidine, zanubrutinib and SCH772984 showed prominent results to cure various gastrointestinal disorders. OBJECTIVES: In this manuscript, we focus on the importance of indazole derivatives in the treatment of various gastrointestinal diseases. RESULTS AND CONCLUSION: In the treatment of IBS, four positions (R1, R2, R3 and R4) of indazole were mainly substituted with aromatic aldehyde/substituted methyl, aromatic acid/formamide, benzamide/ sulfonamide and methyl groups, respectively. In case of diarrhea and metabolic syndrome treatment, substitutions with benzyl/isopropyl/acetaldehyde (R1 position) and carboxamide/ formamide (R2 position) of indazole play a critical role. Also, in the treatment of diabetes melitus, all six positions of indazole derivative were substituted with substituted aryl/alkyl/aromatic acid, substituted formamide, substituted acetamide/hydrazide group, halo aryl, substituted aryl/aromatic acid and a long chain of alkyl-aryl alcohol groups, respectively. In the treatment of gastrointestinal cancers, all six positions of indazole derivative were substituted with benzylamide (R1), octanediamide/ benzamide/formamide (R2), carbaldehyde (R4) and substituted phenyl (R5 and R6) groups, respectively. Six receptors (6NP0, 2YME, 4EFU, 4WZ8, 5U4W and 7KKP) associated with GI disorders (co-crystallized with indazole derivative) were identified. Analysis of the receptors showed that co-crystalized ligand molecules were well-interacted with receptors via pie-pie interaction, coordinate and sigma bonding within 4 Å distance. As per Ramachandran plot analysis, more than 90% of the amino acid residues were present in the most favored region. So, if sufficient focuses are imposed on the development of newer indazole derivatives to treat gastrointestinal diseases, it will work as a boon to society.

Gamma Secretase Inhibitor: Therapeutic Target via NOTCH Signaling in T Cell Acute Lymphoblastic Leukemia.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is a diseased condition of bone marrow and lymphoblast, mainly expressed on T-cell immune phenotype. Diagnosis of TALL patients shows the burden of a large tumour and leukemia cells in the peripheral blood vessel which often infiltrates into the central nervous system. OBJECTIVE: Chemotherapy is considered the primary mode of treatment for this disease, but recent advancements in the molecular understanding of the disease, including NOTCH1 signaling, could offer some alternatives. NOTCH signaling undergoes a non-regulated mutation at NOTCH1 in most T-ALL. Gamma-secretase (GS) plays a key role in blocking of proteolytic activation of NOTCH receptors, which could potentially be a new targeted therapy for this type of leukaemia. This study mainly aims to outline the role of γ-secretase inhibitors via NOTCH signaling in TALL. RESULTS: The role of GSI (γ-secretase inhibitor) in most T-ALL cell lines has been linked to the targeting pathway of NOTCH signaling. Mutation at NOTCH1 has however not served as a predictor of γ-secretase inhibitor sensitivity because of several factors, including gene expression of NOTCH pathway activity. Therefore, despite the promising outcome of this approach in NOTCH-1 activated T-ALL, not all patients with this condition are expected to respond. CONCLUSION: Long-term therapeutic success against cancerous cells is rarely achieved with monotherapy, and even targeting investigational pathways such as NOTCH may require a combination regimen. Ultimately, the optimised use of these new therapeutic agents may become the next tool in our search for an effective 'individualized medicine'.

Recent Advances in the Discovery of GSK-3 Inhibitors from Synthetic Origin in the Treatment of Neurological Disorders.

BACKGROUND: Glycogen synthase kinase 3 (GSK-3) is a serine/threonine kinase enzyme that controls neuronal functions such as neurite outgrowth, synapse formation, neurotransmission, and neurogenesis. The enzyme has two subunits as GSK-3α and GSK-3ß. 4ACC, 1Q3D, 3AFG, 1UV5, and 1Q5K are the important GSK-3 receptors isolated from Homo sapiens and Mus musculus. This enzyme mainly phosphorylates Tau protein with the increased amount in neuronal fibres together with beta-amyloid plaques that cause neuronal diseases like Alzheimer's, Parkinson's and many more. OBJECTIVE: We investigated the developments of various synthetic GSK-3 inhibitors responsible for the prevention and treatment of neurological disorders, like Alzheimer's disease, bipolar disorders, acting as antidepressants, neuroprotective, etc. Results and Conclusion: It has been observed that structures of the GSK-3 inhibitors are comprised of benzopyridine, benzothiazole, pyrazole, pyrazine, dioxolo-benzoxazine, oxadiazole, and benzimidazole in the skeletal with cyclopropyl amide, phenyl carbamothioate, 3-[(propan- 2-yl)oxy]propan-1-amine in the side chain. The molecules were evaluated against the effectivity of GSK-3, human adenosine kinase, cyclin-dependent kinase, and phosphodiesterase-4 along with tail suspension test forced swim test, percent neuronal survival and other cognitive behaviours. The observations confirmed the remarkable effects of the synthesized molecules to conquer Alzheimer, Parkinson's depression, psychosis and other forms of neurological disorders.

Chondroitin: a natural biomarker with immense biomedical applications.

Naturally extracted glycosaminoglycan chondroitin sulphate is the reactive product of N-acetylgalactosamine and d-glucuronic acid. Chondroitin sulfate (CS) extracted from Scophthalmus maximus, H. scabra, E. fraudatrix, M. magnum, and H. mexicana has shown remarkable anticoagulant, articular cartilage repair, corneal lesion healing, antidiabetic, and antiproliferative effects. Also, platinum and strontium nanoparticles of chondroitin sulfate are effective in osteoarthritis and exert anti-HSV2 and anti-angiogenic properties. A combination of chondroitin sulfate and RNA lipolexes demonstrates gene silencing effects in liver fibrosis. Chondroitin sulfate has also been used as a carrier for loxoprofen hydrogel preparation. Oligosaccharides of chondroitin sulfate showed effective inhibition of bovine testicular hyaluronidase enzyme as an antibacterial agent during pregnancy. Monoclonal antibody-recognized chondroitin sulfate A was effectively used to treat ameloblastoma. Selenium-chondroitin sulfate nanoparticles demonstrated positive effects in therapy of Kashin-Beck disease (KBD) and osteoarthritis.

Hydroxamic acid - A novel molecule for anticancer therapy.

Hydroxamic acid is a potent moiety not only in the field of cancer therapy but also as a mutagenic agent. Among the various derivatives of hydroxamic acid, SAHA (Suberoylanilide Hydroxamic Acid) is considered as a potent anticancer agent. Scientists from the different corner synthesized different hydroxamic acid moieties with some straight chain oxazole, thiadiazole, biphenyl moieties in the terminal position. Acetylation and deacetylation of histones of the core proteins of nucleosomes in chromatin play an important role in the regulation of gene expression. The level of acetylation of histones is established and maintained by two classes of enzymes, histone acetyltransferase and histone deacetylases, which have been identified as transcriptional coactivators and transcriptional corepressors, respectively. There is increasing evidence that aberrant histone acetylation has been linked to various malignant diseases. Great efforts are currently underway for the design of more potent and less toxic candidates for the treatment of cancer. In recent years, hydroxamic acid derivatives have attracted increasing attention for their potential as highly efficacious in combating various etiological factors associated with cancer. Our main intention to draw an attention is that this single functional moiety has not only fit in the receptor but also create a diversified activity.