The P-glycoprotein (P-gp/ABCB1) is responsible for a xenobiotic efflux pump that shackles intracellular drug accumulation. Additionally, it is included in the dud of considerable antiviral and anticancer chemotherapies because of the multidrug resistance (MDR) phenomenon. In the search for prospective anticancer drugs that inhibit the ABCB1 transporter, the Natural Product Activity and Species Source (NPASS) database, containing >35,000 molecules, was explored for identifying ABCB1 inhibitors. The performance of AutoDock4.2.6 software to anticipate ABCB1 docking score and pose was first assessed according to available experimental data. The docking scores of the NPASS molecules were predicted against the ABCB1 transporter. Molecular dynamics (MD) simulations were conducted for molecules with docking scores lower than taxol, a reference inhibitor, pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. On the basis of MM-GBSA calculations, five compounds revealed promising binding affinities as ABCB1 inhibitors with ΔGbinding < −105.0 kcal/mol. The binding affinity and stability of the identified inhibitors were compared to the chemotherapeutic agent. Structural and energetical analyses unveiled great steadiness of the investigated inhibitors within the ABCB1 active site throughout 100 ns MD simulations. Conclusively, these findings point out that NPC104372, NPC475164, NPC2313, NPC197736, and NPC477344 hold guarantees as potential ABCB1 drug candidates and warrant further in vitro/in vivo tests.

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With a "less is more" philosophy, a series of 15 chalcone-sulfonamide hybrids were designed anticipating synergistic anticancer activity. The aromatic sulfonamide moiety was included as a known direct inhibitor of carbonic anhydrase IX activity through its zinc chelating property. The chalcone moiety was incorporated as an electrophilic stressor to indirectly inhibit carbonic anhydrase IX cellular activity. Screening by the Developmental Therapeutics Program of the National Cancer Institute, NCI-60, revealed that 12 derivatives were potent inhibitors of cancer cell growth in multiple cell lines and were promoted to the five-dose screen. The cancer cell growth inhibition profile indicated sub-to two-digit micromolar potency (GI 50 down to 0.3 μM and LC 50 as low as 4 μM) against colorectal carcinoma cells, in particular. Unexpectedly, most compounds demonstrated low to moderate potency as direct inhibitors of carbonic anhydrase catalytic activity in vitro, with 4d being the most potent, having an average Ki value of 4 μM. Compound 4j showed ca. six-fold selectivity to carbonic anhydrase IX over the other tested isoforms in vitro. Cytotoxicity of both 4d and 4j in live HCT116, U251, and LOX IMVI cells under hypoxic conditions confirmed their targeting of carbonic anhydrase activity. Elevation of oxidative cellular stress was stipulated from the increase in Nrf2 and ROS levels in 4j-treated colorectal carcinoma, HCT116, cells compared to the control. Compound 4j arrested the cell cycle of HCT116 cells at the G1/S phase. In addition, both 4d and 4j showed up to 50-fold cancer cell selectivity compared to the non-cancerous HEK293T cells. Accordingly, this study presents 4d and 4j being new, synthetically accessible, simplistically designed derivatives as potential candidates to be further developed as anticancer therapeutics. ■ HIGHLIGHTS• Hybrid chalcone-sulfonamides were designed as potential carbonic anhydrase inhibitors. • The derivatives inhibited cancer cell growth in the NCI-60 screen with high potency. • Up to 50-fold selectivity on cancer cells compared to normal cells was demonstrated. • Cell cycle arrest was observed at the G1/S phase in HCT116 colorectal carcinoma cells. • Nrf2 and ROS levels were elevated in response to one of the compounds in HCT116 cells.

Sulphonamide and 1,3,4-oxadiazole moieties are present as integral structural parts of many drugs and pharmaceuticals. Taking into account the significance of these moieties, we herein present the synthesis, single-crystal X-ray analysis, DFT studies, and α -amylase inhibition of probenecid derived two S -alkylphthalimide-oxadiazole-benzenesulfonamide hybrids. The synthesis has been accomplished in high yields. The final structures of both hybrids have been established completely with the help of different spectro-analytical techniques, including NMR, FTIR, HR-MS, and single-crystal X-ray diffraction analyses. In an effort to confirm the experimental findings, versatile quantum mechanical calculations and Hirshfeld Surface analysis have been performed. α -Amylase inhibition assay has been executed to investigate the enzyme inhibitory potential of both hybrids. The low IC 50 value (76.92 ± 0.19 μg/mL) of hybrid 2 shows the good α -amylase inhibition potential of the respective compound. Ultimately, the binding affinities and features of the two hybrids are elucidated utilising a molecular docking technique against the α -amylase enzyme.

The main protease (Mpro) is a potential druggable target in SARS-CoV-2 replication. Herein, an in silico study was conducted to mine for Mpro inhibitors from toxin sources. A toxin and toxin-target database (T3DB) was virtually screened for inhibitor activity towards the Mpro enzyme utilizing molecular docking calculations. Promising toxins were subsequently characterized using a combination of molecular dynamics (MD) simulations and molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. According to the MM-GBSA binding energies over 200 ns MD simulations, three toxins—namely philanthotoxin (T3D2489), azaspiracid (T3D2672), and taziprinone (T3D2378)—demonstrated higher binding affinities against SARS-CoV-2 Mpro than the co-crystalized inhibitor XF7 with MM-GBSA binding energies of −58.9, −55.9, −50.1, and −43.7 kcal/mol, respectively. The molecular network analyses showed that philanthotoxin provides a ligand lead using the STRING database, which includes the biochemical top 20 signaling genes CTSB, CTSL, and CTSK. Ultimately, pathway enrichment analysis (PEA) and Reactome mining results revealed that philanthotoxin could prevent severe lung injury in COVID-19 patients through the remodeling of interleukins (IL-4 and IL-13) and the matrix metalloproteinases (MMPs). These findings have identified that philanthotoxin—a venom of the Egyptian solitary wasp—holds promise as a potential Mpro inhibitor and warrants further in vitro/in vivo validation.

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Resurgence to target L-type voltage-dependent calcium channels has been applied by the synthesis of two series of nifedipine analogues where the ortho-or a meta-nitrophenyl ring is retained. A pre-synthetic molecular docking study with a receptor model followed by molecular alignment has been performed on 47 compounds to predict the most active member. The IC 50 values revealed that some of the compounds are similar to or more active than nifedipine. Substitution of groups at the 3-and 5-positions of the dihydropyridine (DHP) ring gave 3k, which is more active than nifedipine. Our valid three-dimensional quantitative structure-activity relationship (3D-QSAR) model prefigures the influence of lipophilicity, bulkiness and chelating effects of the C3 and C5 substituents. Bulky groups interfere with ring-to-ring hydrophobic interaction with tyrosine (Tyr) 4311 and limit the efficiency of increasing the length of the hydrocarbon chain of esters at the 3-and 5-positions of the DHP ring as an approach to increasing the activity. The presence of a chelating substituent on the phenyl ring at the 4-position of the DHP ring ensures strong binding to the receptor and hence stabilization of the closed-channel conformation. The validation of 3D-QSAR model indicated its proficiency in predicting activity of newly compounds belonging to the same chemical class.Key words calcium channel; dihydropyridine; docking; synthesis; three-dimensional quantitative structureactivity relationship (3D-QSAR) Precise regulation of calcium homeostasis is crucial for many physiological functions.1) Divergent types of calcium channels and pumps can control the influx of calcium ions into cells.2,3) Consequently, targeting calcium channels is advantageously beneficial to yield useful drugs. Ca V 1.2 blockers can be roughly categorized into three different chemical classes: 1,4-dihydropyridine (DHP) derivatives, phenylalkylamine derivatives and benzothiazepine derivatives. Among them, DHP derivatives have the most significant pharmacological importance. For example, amlodipine is among the top-five best selling drugs in the treatment of cardiovascular diseases. Various modulators can potentiate or block calcium entry through L-type calcium channels. [4][5][6] Calcium antagonists have a versatile pharmacological activity such as antihypertensive and antianginal, 7-9) antitumor, 10,11) anti-inflammatory, 12,13) antitubercular, 14,15) anticonvulsant and antithrombotic. 16,17) 1,4-DHPs bind selectively to L-type calcium channel protein, precisely at the transmembrane domain IIIS6 and IVS6 regions of the α1 subunit.18) The twelve approved DHP calcium antagonists developed are vasodilators.19) Vasodilatation is due to the uncoupling of the contractile mechanism of vascular smooth muscle, which requires Ca 2+ . 20)Structure-activity relationship (SAR) of DHP 21) and the clinical usage of nifedipine have promoted us to synthesize two series of nifedipine analogues where the ortho-or a meta-nitrophenyl ring is retained. A pre-synthetic molecular docking st...

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