Newly designed compounds from scaffolds of known actives as inhibitors of survivin: computational analysis from the perspective of fragment-based drug design

Elekofehinti, Olusola Olalekan; Iwaloye, Opeyemi; Olawale, Femi; Chukwuemeka, Prosper Obed; Folorunso, Ibukun Mary

doi:10.1007/s40203-021-00108-8

Cited by 12 publications

(3 citation statements)

References 43 publications

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“…Changes in the position and number of heteroatoms in the molecular skeleton based on fragment design can greatly affect the physicochemical properties, bioactivity, and pharmacokinetics of small molecules. Therefore, the rational use of scaffold hopping strategies based on target structure can improve the success rate of drug candidates [42,43].…”

Section: Scaffold Hopping By Fragment Replacementmentioning

confidence: 99%

In Silico Analysis of USP7 Inhibitors Based on Building QSAR Models and Fragment Design for Screening Marine Compound Libraries

Tan,

Li,

Lai

et al. 2023

Marine Drugs

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USP7 is highly expressed in a variety of tumors and is thought to play a major role in cancer development. However, there are no drugs available to target USP7, so there is a need to develop new USP7 inhibitors. In this study, AutoQSAR, multiple linear regression, and Naive Bayesian models were constructed using 543 compounds and used to analyze marine compounds. After selecting 240 small molecules for molecular docking with Maestro, MOE, and GOLD, better small molecules than the positive compound P217564 were screened. The molecular structure of “1, 2-dibromobenzene” was optimized to improve the binding effect of the protein, and 10 optimized compounds in ADMET performed well during the screening process. To study the dynamic combination of protein–ligand effect consistency with static molecular docking, 100ns molecular dynamics simulations of candidate compound 1008-1, reference compound P217564, and negative-positive GNE2917 were conducted. The results of molecular docking and molecular dynamics simulation analysis showed that compound 1008-1 maintained a stable conformation with the target protein. Thus, the comprehensive analysis suggests that compound 1008-1 could provide new possibilities for USP7 covalent inhibitor candidates.

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Section: Scaffold Hopping By Fragment Replacementmentioning

confidence: 99%

In Silico Analysis of USP7 Inhibitors Based on Building QSAR Models and Fragment Design for Screening Marine Compound Libraries

Tan,

Li,

Lai

et al. 2023

Marine Drugs

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“…A variety of molecular reactivity indicators, including electrophilicity, hardness, softness, electron affinity, ionization potential, and molecular electrostatic potential, were assessed. The following mathematical equations were used to perform the computations as discussed previously [93].…”

Section: Density Functional Theorymentioning

confidence: 99%

Triterpenes from African Antidiabetic Herbs as Inhibitors of DPP-4 and PTP1B Targets: Molecular Modeling Investigation

Ogunyemi,

Gyebi,

Olawale

et al. 2023

Preprint

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African indigenous herbs and medicinal plants are extensively reported for their protective and therapeutic potential against Diabetes. However, most of the constituent phytochemicals that may account for the therapeutic activity are largely uninvestigated. Exploring novel phytochemical–target interactions in silico could help to provide useful insights into the mechanism underpinning the biological activities of these plants and their constituent phytochemicals. The aim of this study was to explore the interactions of terpene struc-tures previously reported from selected African antidiabetic with two emerging drug targets in diabetes. Structure-based virtual screening was used to screen 107 terpene structures against DPP-4 and PTP1B enzymes. The MD simulation, MM-GBSA free energy calculation and DFT were used to clarify the inter-actions of the in silico hits with the target enzymes. Molecular docking, post-docking Prime MM-GBSA analysis revealed the top terpenes with high binding affinity with the active site regions of DPP-4 and PTP1B. Ensemble docking revealed three triterpenes viz: cucurbitacin B (T1), 6-Oxoisoiguesterin (T4) and 20-Epi-isoiguesterinol (T2) as in silico hits which exhibit strong interaction potential with critical residues that define the catalytic triad (Ser630 and His740); oxyanion cavity (Ser631); hydrophobic S1 pocket (Tyr662) and the charged S2 pocket (Arg125) in the active site region of DPP-4. The interactions of these compounds with DPP-4 exhibited structural stability and conformational flexibility during 100 ns full atomistic MD simulation as indicated by the structure dynamics parameters including RMSD, RoG, SASA and hydrogen bond number. The post-MD MM/GBSA calculations further revealed the stability of the triterpene-DPP-4 complexes. Furthermore, Frontier molecular orbital calculations showed that, the triterpenes possess high interaction potential with the enzyme. The triterpenes showed desirable ADMET properties and drug-likeness. Therefore, cucurbitacin B, 6-Oxoisoiguesterin and 20-Epi-isoiguesterinol are recommended for experimental validation.

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“…The global reactivity parameters, including hardness, electronegativity, softness, electron affinity, ionisation potential and quantum moment dipole, were assessed. The calculations were based on the mathematical equations below [32], where the energies of the HOMO and LUMO orbitals are depicted as E (HOMO) and E (LUMO) .…”

Section: Density Functional Theorymentioning

confidence: 99%

Ocimum tenuiflorum L mediated green synthesis of silver and selenium nanoparticles: antioxidant activity, cytotoxicity and density functional theory studies

Olawale¹,

Ariatti²,

Singh³

2022

Adv. Nat. Sci: Nanosci. Nanotechnol.

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Inorganic nanoparticles (NPs) have found extensive application in medicine and pharmaceutics. Although chemical synthesis of NPs is the most commonly employed technique, it is often associated with toxicities due to the nature of the precursors and the experimental conditions used. Hence, there is a need for a safer biosynthetic approach. The current study involves the green synthesis of silver (Ag) and selenium (Se) NPs using an aqueous Ocimum tenuiflorum inflorescence extract. Total phenol and HPLC-MS based phytochemical analysis of the extract was performed. NPs were analysed using UV-visible, and Fourier transform infrared (FTIR) spectroscopy, electron microscopy (EM), x-ray diffraction (XRD) and nanoparticle tracking analysis (NTA). Surface plasmon resonance bands at 433 nm and 285 nm confirmed the synthesis of the Ag and SeNPs, respectively. NPs were monodisperse, small (<65 nm), with good stability and significant antioxidant activity. Cytotoxicity evaluated in the human embryonic kidney (HEK293), cervical carcinoma (HeLa) and breast adenocarcinoma (MCF-7) cells showed a dose-dependent trend with Se possessing better biocompatibility in the normal HEK293 cells than Ag. Density functional theory identified anthocyanins (delphinidin-5-O-beta-d-glucoside and delphinidin-3-O-glucoside) to have the most favourable NP-reducing and stabilising potential from the identified plant compounds.

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Newly designed compounds from scaffolds of known actives as inhibitors of survivin: computational analysis from the perspective of fragment-based drug design

Cited by 12 publications

References 43 publications

In Silico Analysis of USP7 Inhibitors Based on Building QSAR Models and Fragment Design for Screening Marine Compound Libraries

In Silico Analysis of USP7 Inhibitors Based on Building QSAR Models and Fragment Design for Screening Marine Compound Libraries

Triterpenes from African Antidiabetic Herbs as Inhibitors of DPP-4 and PTP1B Targets: Molecular Modeling Investigation

Ocimum tenuiflorum L mediated green synthesis of silver and selenium nanoparticles: antioxidant activity, cytotoxicity and density functional theory studies

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