Letters in Drug Design & Discovery - Volume 21, Issue 3, 2024

The unique properties of nanomaterials (NMs) make them special entities for biomedical innovation and research. Early diagnosis and follow-up of diseases are easily possible with the help of nanotechnology and nanomedicine, which can help combat any medical condition. Surface functionalization with specific molecules might impart marked properties to NMs, leading to the modification of cellspecific interactions within the biological systems. This modification may provide excellent phenomena for innovative drug development. Modified NMs might play essential roles in various applications, i.e., in vivo diagnostics, magnetic resonance imaging (MRI), positron emission tomography (PET), etc. Functionalization of NMs with appropriate ligands, small molecules, or polymers assigned them enhanced stability, biocompatibility, and functionality for their novel and improved biological applications. Surface functionalized NMs might display enhanced antimicrobial, antidiabetic, and drug delivery potential for various applications. Different studies reported the potential of functionalized metallic nanoparticles in regenerative medicines. Conjugation of NMs with various molecules such as peptides, small ligands, polysaccharides, proteins, saturated and polyunsaturated fatty acids, siRNA, plasmids, and DNA, might be achieved by various reactions. Biomolecule-conjugated nanoparticles result in the production of hybrid NMs with specific and novel biological interactions in biological systems. Chemical treatment methods are considered among the most trusted and efficient functionalization methods. Some commonly used techniques and strategies of functionalization involve grafting to and grafting from methods, ligand exchange technique, covalent bonding, chemisorption, non-covalent interactions, electrostatic adsorption, etc. This brief review is dedicated to the surface functionalization of NMs with the latest development.

Cancer is the most malignant chronic disease worldwide, with a high mortality rate. It can be treated with conventional therapies such as chemotherapy and immunotherapy, but these techniques have several side effects, limiting their therapeutic outcome and reducing application. Recently, a promising method of drug delivery has been devised to minimize side effects and induce potential benefits during treatment. The targeted drug delivery system (TDDS) is one of the established drug delivery methods using nanoparticles, crossing different biological barriers, targeting a specific diseased site, and resulting in sustained drug release. The current research introduces a plethora of nanoparticles that can be implemented to deliver or target drugs to a particular site, such as polymeric nanoparticles (PLGA, PLA, chitosan), metal-based nanoparticles (gold, iron oxide), carbon-based nanoparticles (CNTs, graphene), bio nanoparticles (liposomes, micelles) and ceramic nanoparticles (mesoporous-based silica, calcium phosphate). Most of them are proven to be very efficient in targeting the desired site and causing fatal damage to the tumor cells. Zinc oxide (ZnO) is a nano compound, that shows a wide range of favorable properties, making it widely acceptable for biomedical applications. This review focuses on TDDS using ZnO as a drug carrier, followed by factors affecting TDDS such as drug loading, encapsulation efficiency, cell viability, and zeta potential. The target mechanism of TDDS for cancer therapy has also been discussed, indicating a better alternative for clinical treatment. This approach also presents certain challenges besides the potential for oncology.

Tetrahydrocarbazoles (THCz) are widespread in numerous indole alkaloids and have been reported since time for exhibiting profound pharmacological potential. Many pharmaceuticals drugs have tetrahydrocarbazole nucleus in their structure e.g. vinca alkaloids (Vincristine, Vinblastine, Vinorelbine), Frovatriptan, (R)-Ramatroban, Ondansetron, etc. that are used in various multifactorial diseases. In this review article, the anticancer potential of tetrahydrocarbazole based derivatives has been covered, enumerating their vast journey from the year 2000 to 2021. Since the last twenty-one years, tetrahydrocarbazoles have been a matter of focus among researchers worldwide, whereby several novel tetrahydrocarbazole derivatives have been synthesized and reported for their anticancer potential against various cancer cell lines. Tetrahydrocarabzole and its derivatives have exhibited profound anticancer potential mediated via various cancer pathways like apoptosis, cell cycle arrest, microtubule inhibition, Nrf2 Modulators, DNA intercalators, pERK and pRb phosphorylation, VEGF (Vascular Endothelial Growth Factor) and TNF-α inhibition, TPSO (translocator protein), Histone Deacetylase (HDAC) Inhibitors also discussed. The present review entails the synthesis, SAR studies, and anticancer mechanism of tetrahydrocarbazoles derivatives reported in review literature till date, and would provide a strong database to the medicinal chemist world over in discovering newer potential anticancer agent against various types of cancer diseases.

Computational fluid dynamics (CFD) is a feasible tool to examine and troubleshoot different types of equipment utilized in the pharmaceutical industry or healthcare. As a large number of fluids are processed by unit operations, even some increments in performance and efficiency may escalate profits and reduce costs. CFD methods are primarily used in the automobile and aerospace industries, but in the current era, this technology is extensively applied in the pharmaceutical and chemical industries and has become an important tool for process design scaleup and optimization. CFD is a numerical approach utilizing CFD software to solve equations numerically. This review focuses on the diverse utilization of CFD in the pharmaceutical field and current applications in the COVID 19 pandemic, a recent health crisis that is intimidating the world.

Background: Benzimidazole (Benz-fused bicyclic ring system) is the most versatile class of heterocyclic compounds due to its numerous applications in industrial and synthetic organic chemistry because of its many biological actions. Benzimidazole analogs have been used to discover various medical problems, such as cancer, bacterial infections, fungi infections, etc. Researchers are studying nitrogencontaining hybrid heterocyclic compounds because they provide a broad range of therapeutic potential and have minimal side effects. Objective: The current literature review emphasizes recent developments in the design of new benzimidazole derivatives as possible anticancer agents with their relationship between structure and activity, which will give insight into the future design of more active benzimidazole molecules. Results: The present review consists of synthetic protocols for the synthesis of benzimidazole derivatives along with their pharmacological potentials and structure-activity relationship in correlation with synthetic molecules to provide a depth view of the work done on benzimidazole. Conclusion: It would be significant for further research in developing better drug molecules representing a potent derivative of medicinal agents.

Molecular docking is a structure-based computational method that generates the binding pose and affinity between ligands and targets. There are many powerful docking programs. However, there is no single program that is suitable for every system. Hence, an appropriate program is chosen based on availability, need, and computer capacity. Molecular docking has clear steps that should be followed carefully to get a good result. Molecular docking has many applications at various stages in drug discovery. Although it has various application areas, it is commonly applied in virtual screening and drug repurposing. As a result, it is playing a substantial role in the endeavor to discover a potent drug against COVID-19. There are also approved drugs in the pharmaceutical market that are developed through the use of molecular docking. As the accessible data is increasing and the method is advancing with the contribution of the latest computational developments, its use in drug discovery is also increasing. Molecular docking has played a crucial role in making drug discovery faster, cheaper, and more effective. More advances in docking algorithms, integration with other computational methods, and the introduction of new approaches are expected. Thus, more applications that will make drug discovery easier are expected.

Background: With the emerging resistance to mainstream insecticides, it is necessary to develop new insecticides to tackle the problem of pest threat. Diamide insecticides are widely studied because of their broad spectrum of activities, high efficiency, and low toxicity. Most thioether and oxide sulfide-containing compounds have a wide range of biological activities in agricultural chemicals.Objective: The main purpose of the study was to explore novel thioether and oxide sulfide-containing diamide compounds possessing outstanding insecticidal activity.Methods: Based on the "active substructure replacing" method by introducing methylthio groups, 29 sulfide-containing diamide compounds were designed and synthesised. The structures of all synthetic compounds were confirmed by ¹H-NMR, ¹³C-NMR and HRMS. Moreover, the biological activities of all the compounds were tested.Results: The preliminary bioassay indicated that most of the new compounds did not exhibit better activity than the reference insecticide cyproflanilide. However, compounds 18a and 23a showed markedly potent activity against Tetranychus cinnabarinus at 100 mg/L, which was better than cyproflanilide since these compounds possessed 2-methyl-4-cyanophenyl, which might be the reason for their better internal absorption in the plant.Conclusion: The structure-activity relationship showed that some compounds were of potential value to be developed as novel insecticides, but the majority of compounds did not show superior insecticidal activity than cyproflanilide.

Background: Quinoline derivatives have evinced their biological importance in targeting bacteria by inhibiting Dihydrofolate reductase. H2SO4 was successfully applied as an acid catalyst for a green, efficient, and one-pot solvent-free synthesis of quinoline derivatives using sonochemistry approach from various aromatic amines and glycerol with affording yield up to 96% within 6-10 min.Objective: In this study, the synthesis, characterization, and biological assessment of fifteen quinoline derivatives (1-15) as potential DHFR inhibitors were carried out. The target compounds were docked to study the molecular interactions and binding affinities with the 1DLS enzyme.Methods: The synthesized molecules were characterized using IR, MASS, and ¹H and ¹³C NMR. The Insilico molecular docking study was carried out through target Human Dihydrofolate Reductase (DHFR) retrieved from a protein data bank having PDB ID: 1DLS and the antimicrobial activity of all synthesized compounds were tested against Human Dihydrofolate Reductase(DHFR) enzyme by using in-vitro DHFR assay kit.Results: The molecular docking results revealed that compounds 2 and 6 have the lowest binding energy and good binding affinity with the DHFR enzyme. In-silico ADMET predictions revealed that all bestscored compounds had good absorption and drug-like properties for potential use as DHFR inhibitors to treat bacterial infection. The in vitro studies revealed that compounds 2 and 6 show potent DFHR inhibitory activity against gram-positive and gram-negative with IC50 = 12.05 ± 1.55 μM and 10.04 ± 0.73 μM, respectively. While compounds 12, 13, and 15 exhibited moderate antimicrobial activity through DHFR inhibition with IC50= 16.33 ± 0.73 μM, 17.02 ± 1.55 μM, and 18.04 ± 1.05 μM, respectively.Conclusion: This environmentally benign sonochemistry-based approach for synthesizing quinoline derivatives could be affordable for large-scale production and become a potential lead candidate for developing a new quinoline-based antimicrobial agent.

Background: Although it has been established that activating adenosine monophosphateactivated protein kinase (AMPK) inhibits cell proliferation in several cells, it is unknown whether AMPK is involved in inhibiting biliary fibroblast growth. Objective: The objective of this study is to specifically investigate the influence of AMPK isoforms on proliferation. Methods: To further address its underlying molecular mechanisms, primary cultured rat biliary fibroblasts were transfected with sequence-specific AMPK1 or AMPK2 siRNA. Results: Our findings show that knocking down AMPK2 greatly increased the proliferation of primary cultured biliary fibroblasts, accompanied by the activation of mTOR, an increase in S-phase kinaseassociated protein 2 (Skp2) expression, and a decrease in p27 protein levels. AMPK2 inhibition-triggered Skp2 overexpression and concomitant p27 decrease, as well as biliary fibroblast proliferation, were reversed by rapamycin inhibition or previous silencing of Skp2 production by targeted small interfering RNA (siRNA) transfection. Conclusion: We concluded that AMPK2 regulates the mTOR/Skp2/p27 signaling pathway and causes endogenous suppression of primary cultured biliary fibroblast growth. The reduction of biliary fibroblast proliferation by AMPK2 could be a potential method in treating benign biliary stricture (BBS).

Background: A schiff base is generally a bi- or tri-dentate ligand capable of forming stable complexes with transition metals. Schiff base complexes have synthetic flexibilities and biological activity against various diseases. Objective: In the current study, Schiff bases compounds (PV1 - PV5) were synthesized from 4-methyl-1- benzene sulfonyl chloride. Subsequently, the synthesized products were analyzed for their antibacterial activity. Methods: Schiff base is a nitrogen analog with a carbonyl group. The reaction that results in the formation of new complexes involves the condensation of carbonyl compounds with an amine group. Furthermore, thin layer chromatography, FT-IR spectroscopy, and ¹H-NMR were performed for product characterization. Results: All five complexes were successfully synthesized and some of the compounds demonstrated antibacterial, antifungal, anti-inflammatory and analgesic properties. Conclusion: The results confirmed the structure and presence of functional groups as per the scheme of synthesis. These synthesized compounds have the potential to treat the studied diseases and could be used as therapeutic candidates if further research is done.

Background: Apoptosis of brain cells (neurons and glia) has a crucial role in humans' pathology of traumatic brain injury (TBI). So, a decrease in the apoptosis rate can potentially reduce the harmful effects and lead to better functional outcomes. Drug repurposing by computational methodologies like protein-ligand docking allows us to make drug discovery more efficient and less expensive. Objective: In the current study, we used the methodology to study the inhibitory effect of thousands of FDA/non-FDA approved, investigational compounds on caspase 3 as one of the most important members of the cell apoptosis pathway. Methods: Molecular docking and pharmacokinetic properties calculations were done. The molecular dynamics (MD) simulations of all complexes and free caspase 3 were carried out. We carried out docking experiments using in silico methods and docked a pool of medications to the active site of the human caspase-3 X-ray structure. The best compounds were selected and subjected to pharmacokinetic analysis, molecular simulation, and free energy calculations. Results: Finally, 6 components (Naldemedine, Celastrol, Nilotinib, Drospirenone, Lumacaftor, and R- 343) were selected as the best in terms of structural and pharmaceutical properties, low toxicity that can be administered orally for the preclinical and clinical future investigations.

Background: Epidermal growth factor receptor (EGFR) is a validated and therapeutically amenable target, and inhibition of the EGFR signaling pathway has emerged as an attractive target for cancer therapy.Methods: The present work was designed to synthesize and evaluate the antiproliferative activity of a novel series of 3,9-dioxatetraasteranes as potential inhibitors of EGFR. All target compounds were evaluated for antiproliferative activity in vitro against A549 and HepG2 cell lines.Results: Among the target compounds, compound B13 displayed the most potent antiproliferative activity against A549 with IC50 = 4.31 μM and HepG2 with IC50 = 6.92 μM. In addition, a molecular docking study was performed to investigate the binding mode and binding capacity with EGFR (PDB code: 1M17). Conclusion: The results indicated that 3,9-dioxatetraasteranes may be promising potential EGFR inhibitors.

Background: The most significant antioxidant enzymes are glutathione peroxidase (GSHPx), catalase (CAT), and superoxide dismutase (SOD) have a significant role in the scavenging of free radicals, but overexpressing of these enzymes can have deleterious effects. Therefore, compounds outside the body must suppress this enzyme's growth rate. Several previous studies have stated that Piper betle L. has high antioxidants and inhibits enzyme activity, including allypyrocatechol.Objectives: The current study aimed to evaluate the molecular mechanism of allylpyrocatecachol with SOD, CAT, and GSHPx and determine the lead compounds' potential against some antioxidant enzymes by an in silico approach.Methods: Allylpyrocatechol was docked to SOD, CAT, and GSHPx enzyme using Autodock4 tools. An evaluation of receptor-ligand interactions was conducted based on comparing binding affinity, the accuracy of involved amino acid residues, and gallic acid as a positive control ligand.Results: By in silico analysis showed that the binding affinity between the ligand and the three receptors were -4.3, -6.8, and -4.5 kcal/mol for the SOD, CAT, and GHSPx receptors, respectively.Conclusion: This finding indicates that Allylpyrocatechol has a promising candidate as a compound to inhibit antioxidant enzyme activity. It can be seen from the accuracy of the amino acids residue involved and the value of the binding affinity compared to the positive control ligand.

Background: Acetaminophen (APAP) or paracetamol is a widely used over-the-counter, analgesic (common conditions treated include headaches, backache, toothache, muscle aches, arthritis, sore throat etc.) and antipyretic drug. It can be administered orally, in the form of a tablet (plain, effervescent, orodispersable, etc.) or liquid, rectally in the form of a suppository or by injection (intravenously or intramuscularly). It is well absorbed orally with a plasma elimination half-life ranging from 1 to 4 h. The modified release oral formulation can prolong its therapeutic effects by maintaining APAP average plasma concentrations. Objective: In the context of this work, two APAP formulation tablets with different geometries were produced from standard pharmaceutical excipients to investigate the role of altered tablet geometry in modified oral drug delivery. Methods: APAP tablets were prepared by direct compression, using hydroxypropyl methylcellulose (HPMC K15M), polyvinylpyrrolidone (PVP, MW: 55,000) and magnesium stearate, as ingredients. The release profiles were probed in aqueous dissolution media (pH 1.2 and 6.8) to simulate the conditions in the gastrointestinal tract in a United States Pharmacopeia (USP) dissolution paddle apparatus II and analyzed using an ultraviolet (UV) spectrophotometer (λmax = 244 nm). Results: The results indicated that the tablets were within the acceptable range of all evaluation parameters (tablet dimensions, drug content, weight variation, and breaking force) as defined by the international standards stated in the US Pharmacopoeia. The dissolution results showed that the APAP’s release profile was controlled by the tablets’ different geometries and, specifically the surface area (SA) and the surface area/volume (SA/V) ratio of the different tablets. The tablets with smaller SA/V ratios and SA showed slower drug release, indicative of a modified release motif. Conclusion: Altered tablet geometry plays an important role in APAP-modified oral drug delivery.

Background: Candida albicans is a fungal species associated with opportunistic fungal infectious agents in human populations, especially in immunocompromised patients, such as transplant patients, HIV-positive patients, chemotherapy patients, and low-birth-weight newborns. The death rate for systemic Candida illnesses ranges from 29 to 76 percent. Only a few medications are available to treat them, such as amphotericin B, fluconazole, terbinafine, and caspofungin, which have adverse reactions and are harmful. Objective: The goal of this research is to apply specialized bioinformatics approaches, such as molecular docking, scaffold hopping, virtual screening, pharmacophore modeling, and molecular dynamics (MD) simulation, to discover possibly novel and potent therapeutic drug candidates against Candida albicans in a shorter period and at a low cost. Methods: MDPI, MayBridge, Hitfinder, Mcule library, SQLite Database, DrugBank, ZINC, and NCI database were used to perform pharmacophore modeling, scaffold hopping, virtual screening, docking, and ADMET characteristics study against NMT. The molecular dynamics simulations for the best ten docked protein-ligand complexes were examined to determine the stability of protein-ligand interactions during a 200 ns simulation period, demonstrating their potential for lead molecule production via more improvement and experimental verification. Results: We have identified that compounds DB01940 ((3R,4R)-3-(4-hydroxybenzamido)azepan-4-yl 4- (2-hydroxybenzoyl)benzoate), DB01772 (3-(3-{[(2S)-2,3-dihydroxypropyl]amino}phenyl)-4-(5-fluoro-1- methyl-1H-indol-3-yl)-2,5-dihydro-1H-pyrrole-2,5-dione), and NCI5485 (1,3-bis((7-chloro-4- quinolinyl)amino)-2-propanol) could be more promising Candida albicans NMT inhibitors. Conclusion: In conclusion, these compounds have the potential to be effective anti-NMT medicines. The results demonstrated that our computational technique found some potential and effective NMT inhibitors that may be tested in clinical trials.

Background: SARS-CoV-2 was reported to enter cells via binding to ACE2, followed by its priming by TMPRSS2. Hence the inhibition of TMPRSS2 may block or decrease the severity of SARSCoV- 2, making TMPRSS2 an attractive target for COVID-19. fXIa has a similar binding pocket as TMPRSS2, implying the possibility of fXIa inhibitors being TMPRSS2 inhibitors. Methods: In order to find potential TMPRSS2 inhibitors, molecular docking of known fXIa inhibitors was performed. Molecular dynamics simulations and MM/GBSA were conducted on representative compounds with characteristic binding modes. R-group enumeration was used to generate compounds with better binding interactions. Results: Three scaffolds can make hydrogen bonds with Gly439 and Ser441, and form the chloride– Tyr474 interactions at S1 pocket as well. Further structure optimization of one scaffold found that two compounds have better docking scores and lower binding free energies. Conclusion: Compounds R1a and R1b can be taken as potentially reversible inhibitors of TMPRSS2. Our results could provide insight into both the discovery and lead optimization of TMPRSS2 inhibitors.

Background: 2-(1-(1,3,4-thiadiazol-2-yl)piperidin-4-yl) ethan-1-ol analogues represent novel glutaminase 1 inhibitors. Their exemplary antineoplastic efficacy underscores their prospective utility in glioblastoma chemotherapy. Objective: This study aimed to elucidate 2D and 3D-QSAR models that authenticate the antineoplastic efficacy of ethan-1-ol analogues and delineate optimal structural configurations conducive to new pharmaceutical design. Methods: The Heuristic Method (HM) was employed for the development of a 2D-linear QSAR paradigm, whilst the Gene Expression Programming (GEP) algorithm was employed for a 2D-nonlinear QSAR paradigm. Concurrently, the CoMSIA methodology was deployed to scrutinize the nexus between pharmaceutical structure and potency. An ensemble of 200 nascent anti-glioma ethan-1-ol compounds was conceptualized, and their potency levels were prognosticated via chemical descriptors and molecular field delineations. Pharmaceuticals epitomizing peak potency were earmarked for molecular docking validation. Results: The empirical modeling exhibited pronounced superiority with the 3D paradigm, succeeded by the GEP nonlinear paradigm and culminated with the HM linear model. The 3D paradigm was characterized by a robust Q2 (0.533), R2 (0.921), and F-values (132.338) complemented by a minimal SEE (0.110). The molecular descriptor MNO coupled with the hydrogen bond donor field facilitated novel pharmaceutical conceptualizations, leading to the identification of the quintessential active molecule, 24J.138, lauded for its superlative antineoplastic attributes and docking proficiency. Conclusion: The orchestration of bidimensional and tridimensional paradigms, synergized by innovative amalgamation of contour maps and molecular descriptors, provides novel insights and methodologies for the synthesis of glioblastoma chemotherapeutic agents.