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Molecular Modelling and Virtual Screening to Identify New Piperazine Derivatives as Potent Human 5-HT1A Antagonists and Reuptake Inhibitors

Ayipo YO, Alananzeh WA, Yahayaa SN, Mordi MN

Comb Chem High Throughput Screen, 2022 May 24.
PMID: 35611784 DOI: 10.2174/1386207325666220524094913

BACKGROUND: Serotonin/5-HT antagonist and reuptake inhibitors (SARIs) ameliorate depression by increasing the terminal 5-HT through the activation of somatodendritic 5-HT1A autoreceptors. In addition to their therapeutic application as standalone antidepressants, they are co-administered with selective serotonin reuptake inhibitors (SSRI) to improve unpleasant side effects associated with SSRI-treated depression. However, only a few of the atypical antidepressants are available and not without some serious aftereffects. This study aims at the identification of novel promising SARIs using computational chemistry and high throughput screening.
METHODS: Pharmacophore features were modelled using LigandScout 4.3 and validated through the area under curve (AUC), enrichment factor (EF) and Guner-Henry (GH) scores. Molecular docking was employed for virtual screening against modelled human 5HT1A homology receptor, molecular dynamics simulations and ADMET predictions.
RESULTS: The adopted pharmacophore possesses AUC, EF and GH scores of 0.7, 30.9 and 0.6 respectively, thus validated and used for molecular database screening. The modelled 5-HT1A homology receptor, validated using RCSB structure validation protocols, was employed for molecular docking and dynamics simulations. From the IBScreen database, the ligands, STOCK6S-36853, STOCK7S-36094, STOCK3S-94557, STOCK7S-28769 and STOCK5S-36248 interacted more strongly against the 5-HT1A receptor with docking scores of -8.735, -8.677, -8.140, -7.911 and -7.710 kcal/mol, and binding free energy of -29.72, -38.87, -29.85, -7.65 and -34.71 kcal/mol respectively, compared to fluoxetine and trazodone (positive controls) while albendazole and metformin (negative controls) scored least. They demonstrated good stability, satisfy the BDDCS RO5 and thus, are identified as potent SARIs.
CONCLUSION: The study represents a cost-effective, faster and environmentally friendly approach to the discovery of promising SARI antidepressants for further translational study.
N-substituted tetrahydro-beta-carboline as mu-opioid receptors ligands: in silico study; molecular docking, ADMET and molecular dynamics approach

Alananzeh WA, Al-Qattan MN, Ayipo YO, Mordi MN

Mol Divers, 2024 Jun;28(3):1273-1289.
PMID: 37133710 DOI: 10.1007/s11030-023-10655-1

Manipulating intracellular signals by interaction with transmembranal G-protein-coupled receptors (GPCRs) is the way of action of more than 30% of available medicines. Designing molecules against GPCRs is most challenging due to their flexible binding orthosteric and allosteric pockets, a property that lead to different mode and extent of activation of intracellular mediators. Here, in the current study we aimed to design N-substituted tetrahydro-beta-carbolines (THβC's) targeting Mu Opioid Receptors (MORs). We performed ligand docking study for reference and designed compounds against active and inactive states of MOR, as well as the active state bound to intracellular mediator of Gi. The reference compounds include 40 known agonists and antagonists, while the designed compounds include 25,227 N-substituted THβC analogues. Out of the designed compounds, 15 compounds were comparatively having better extra precision (XP) Gscore and were analyzed for absorption, distribution, metabolism, and excretion-toxicity (ADMET) properties, drug-likness, and molecular dynamic (MD) simulation. The results showed that N-substituted tetrahydro-beta-carbolines with and without C6-methoxy group substitutions (THBC/6MTHBC) analogues of A1/B1 and A9/B9 have relatively acceptable affinity and within pocket-stability toward MOR compared to the reference compounds of morphine (agonist) and naloxone (antagonist). Moreover, the designed analogues interact with key residue within the binding pocket of Asp 147 that is reported to be involved in receptor activation. In conclusion, the designed THBC analogues represent a good starting point for designing opioid receptor ligands other than morphinan scaffold, that have good synthetic accessibility which promotes feasible structural manipulation to tailor pharmacological effects with minimal side effects.
Fulltext Pathomechanisms, therapeutic targets and potent inhibitors of some beta-coronaviruses from bench-to-bedside

Ayipo YO, Yahaya SN, Alananzeh WA, Babamale HF, Mordi MN

Infect Genet Evol, 2021 Sep;93:104944.
PMID: 34052418 DOI: 10.1016/j.meegid.2021.104944

Since the emergence of their primitive strains, the complexity surrounding their pathogenesis, constant genetic mutation and translation are contributing factors to the scarcity of a successful vaccine for coronaviruses till moment. Although, the recent announcement of vaccine breakthrough for COVID-19 renews the hope, however, there remains a major challenge of accessibility to urgently match the rapid global therapeutic demand for curtailing the pandemic, thereby creating an impetus for further search. The reassessment of results from a stream of experiments is of enormous importance in identifying bona fide lead-like candidates to fulfil this quest. This review comprehensively highlights the common pathomechanisms and pharmacological targets of HCoV-OC43, SARS-CoV-1, MERS-CoV and SARS-CoV-2, and potent therapeutic potentials from basic and clinical experimental investigations. The implicated targets for the prevention and treatment include the viral proteases (Mpro, PLpro, 3CLpro), viral structural proteins (S- and N-proteins), non-structural proteins (nsp 3, 8, 10, 14, 16), accessory protein (ns12.9), viroporins (3a, E, 8a), enzymes (RdRp, TMPRSS2, ADP-ribosyltransferase, MTase, 2'-O-MTase, TATase, furin, cathepsin, deamidated human triosephosphate isomerase), kinases (MAPK, ERK, PI3K, mTOR, AKT, Abl2), interleukin-6 receptor (IL-6R) and the human host receptor, ACE2. Notably among the 109 overviewed inhibitors include quercetin, eriodictyol, baicalin, luteolin, melatonin, resveratrol and berberine from natural products, GC373, NP164 and HR2P-M2 from peptides, 5F9, m336 and MERS-GD27 from specific human antibodies, imatinib, remdesivir, ivermectin, chloroquine, hydroxychloroquine, nafamostat, interferon-β and HCQ from repurposing libraries, some iron chelators and traditional medicines. This review represents a model for further translational studies for effective anti-CoV therapeutic designs.
Structural modelling and in silico pharmacology of β-carboline alkaloids as potent 5-HT1A receptor antagonists and reuptake inhibitors

Ayipo YO, Alananzeh WA, Ahmad I, Patel H, Mordi MN

J Biomol Struct Dyn, 2023;41(13):6219-6235.
PMID: 35881145 DOI: 10.1080/07391102.2022.2104376

Serotonin (5-HT) antagonists and reuptake inhibitors (SARIs) are atypical antidepressants for managing major depressive disorder. They are oftentimes applied as adjuvants for ameliorating aftereffects of SSRI antidepressants including insomnia and sexual dysfunction. The few available candidates of this class including lorpiprazole and trazodone also display some daunting side effects, making a continuous search for improved alternatives essential. Natural β-carboline alkaloids (NβCs) are interestingly renowned with broad pharmacological spectrum against several neuropsychiatric disorders including depression. However, their potentials as SARIs remain underexplored. In this study, 982 NβCs retrieved from the Ambinter-Greenpharma (Amb) database were virtually screened for potent SARI alternatives using computational and biocheminformatics approaches: homology modelling of 5-HT1A receptor, Glide HTVS, SP and XP molecular docking, molecular dynamics (MD) simulation, ADMET and mutagenicity predictions. The homology receptor was validated as a good representative of human 5HT1A receptor using the RCSB structure validation and quality protocols. From the virtual screening against the 5-HT1A receptor, Amb ligands, Amb18709727 and Amb37857532 showed higher binding affinities by XP scores of -8.725 and -7.976 kcal/mol, and MMGBSA of -87.972 and -107.585 kcal/mol respectively compared to lorpiprazole, a reference SARI with XP score and MMGBSA of -6.512 and -62.788 kcal/mol respectively. They maintained ideal contacts with pharmacologically essential amino acid residues implicated in SARI mechanisms and expressed higher stability and compactness than lorpiprazole throughout the trajectories of 100 ns MD simulation. They also displayed interesting ADME, druggability, low toxicity and mutagenicity profiles, ideal for CNS drug prospects, thus, recommended as putative SARI candidates for further study.Communicated by Ramaswamy H. Sarma.