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Subject: search.filters.subject.Molecular docking

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    Structure-based Design of Coumarin Moieties as Sustainable Inhibitors of Diabetes Mellitus Type 2
    (2025) Opebiyi, O. T.; Oduselu, G.O.; Ogunnupebi, T. A.; Elebiju, O. F.; Adekoya, Joseph Adeyemi; Ajani, O. O.
    The search for novel and more potent antidiabetic agents globally is due to the increase in insulin resistance, and more type 2 diabetes patients become susceptible to secondary compilations. Many pharmacologically active compounds are organic, mostly heterocyclic compounds, accounting for about 85% of Food and Drug Administration (FDA)-approved drugs. An example of a heterocyclic compound is coumarin, a benzopyrone group containing oxygen heteroatoms. Coumarin has been reported to possess several pharmacological properties, and combining coumarin with other compounds has made coumarin more potent. Computer-aided techniques have helped improve the design of potential drug candidates. Using computer-aided techniques, coumarin moieties were investigated for antidiabetic activities for future drug design. Coumarin template was used to search for ligand library on PubChem, an open chemistry database at the National Institutes of Health (NIH); 1653 compounds were downloaded with acarbose and metformin in SDF format, 1632 compounds, acarbose and metformin were successfully prepared, and then docked against human pancreatic alpha-amylase (Protein Data Bank- PDB ID: 4GQR) with Autodock vina. The qualitative structural assessment of the best hits from this molecular docking of a ligand library, acarbose and metformin was done. The functional groups present in this best hits, acarbose and metformin were used to generate 15 novel coumarin derivatives. The designed compounds were also docked against 4GQR, and their chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were conducted. It was observed that 11 of the designed compounds had the lowest binding affinity than the co-crystalized ligand of 4GQR. The best hits compounds from the docking studies were 2g, 2f, 1a and 3e, and the ADMET studies predicted that compounds 1a, 3b, 3c and 3a had better pharmacokinetic and toxicity profiles. This promising result suggests that the designed compounds, particularly 1a, 3b, 3c and 3a, have the potential to be further optimized, synthesized and developed as potent antidiabetic agents, offering a hopeful future for diabetes treatment.
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    MOLECULAR DOCKING, LIGAND QUALITY AND ANTIPLASMODIAL EVALUATION OF BENZAMIDE, COUMARIN AND BENZODIAZEPINE ANALOGS
    (Covenant University Ota, 2025-04) ADEBAYO GLORY PIPELOLUWA; Covenant University Thesis
    Malaria chemotherapy is an essential strategy for malaria elimination but resistance has challenged existing antimalarials, including frontline artemisinin combination therapy (ACT); hence, new antimalarial drugs must be discovered and developed. This study investigated the antiplasmodial efficacy and cytotoxicity through in vitro models while also testing the antiplasmodial efficacy, and the in vivo acute toxicity of benzamide, coumarin and benzodiazepine analogss. This study also evaluated the ligand quality of the molecules and their possible Plasmodium falciparum protein targets. Three molecules, 4- amino-N-hydroxybenzamide (AHB), ethyl 2-oxo-2H-chromene-3-carboxylate (ECC), and 2,2,4-trimethyl-2-3-dihyro-1H-benzo[b][1,4] diazepine (BDZ) were screened for their in vitro antiplasmodial activities tested against P. falciparum 3D7 standard strain using the SYBR Green Dye I measuring IC50 and their cytotoxicities against MCF-7 breast cancer cells using the [3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay. Their antiplasmodial efficacies were determined using Peter’s 4-day suppressive test against Plasmodium berghei in M. musculus while acute toxicities were investigated in the Mus musculus (mice). Ligand qualities were determined using ligand efficiency metrics, and molecular docking was conducted to determine the ligand interactions between ECC and the following enzymatic proteins, P. falciparum dihydroorotate dehydrogenase (PfDHOH) and P. falciparum purine nucleoside phosphorylase (PfPNP); and the molecular interaction between BDZ and PfDXR - Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase, P. falciparum falcipain-2 and P. falciparum plasmepsin X (PfPMX). AHB showed no cytotoxicity against MCF-7 at (CC50) = 277.7 μM, while ECC showed inhibition with CC50= 3.930 μM, and BDZ showed no cytotoxicity CC50= 7373 μM. The in vitro antiplasmodial activity showed potency at (AHB)IC50 = 0.0020 ± 0.008 μM, (ECC) IC50= 0.0010 ± 0.002 μM, (BDZ) IC50= 0.0036 ± 0.003 μM respectively. BDZ showed the highest selectivity index at > 200,000, suggesting that it exhibited the best safety/efficacy among the three compounds. AHB displayed LD50 = >5000 mg/kg while ECC and BDZ displayed LD50 = 3162.28 mg/kg. Histopathological examinations showed non-toxicity by the three analogs on the liver and kidney of M. musculus. The percentage suppression of AHB (80.53 ± 3.26 %) at 400 mg/kg, was comparable to the standard chloroquine (81.71 ± 1.82 %) at 100 mg/kg where the mean survival time for both exceeded 30 days. ECC and BDZ showed excellent efficacies (70.98 ± 20.89 % and 83.66 ± 11.67 %) at 200 mg/kg, comparable to chloroquine 80.97 ± 5.82 %. The chemosuppression values for AHB and BDZ were significant at P value < 0.05. The ligand quality of ECC and BDZ displayed good Ligand Efficiency compared to chloroquine and artemisinin and higher enzyme affinities, and ligand efficiency dependent lipophilicity than the standard drugs. ECC and BDZ displayed good characteristics. The docking studies displayed strong hydrophobic interactions between ECC, PfDHODH, and PfPNP, suggesting good potency. BDZ’s binding with PfDXR, Pffalcipain-2, and PfPMX also displayed potency derived from hydrophobic and hydrogen interactions. Conclusively, this study showed AHB, ECC and BDZ were non-toxic to mammalian cells rodents’ liver and kidneys. These molecules exhibited good antiplasmodial inhibitory potential against both P. falciparum in vitro and P. berghei in vivo. ECC and BDZ displayed high ligand efficiency and strong molecular interactions with their protein targets. Therefore, all three analogs can be moved for further optimization in drug development.