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All Journal Journal of Molecular Docking Borneo Journal of Pharmacy
Fabian Audu Ugbe
Ahmadu Bello University
Medicine & Pharmacology

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Molecular Docking Screening and Pharmacokinetic Studies of Some Boron-Pleuromutilin Analogues against Possible Targets of Wolbachia pipientis Fabian Audu Ugbe; Gideon Adamu Shallangwa; Adamu Uzairu; Ibrahim Abdulkadir
Journal of Molecular Docking Vol. 2 No. 1 (2022): Journal of Molecular Docking
Publisher : Institute for Research and Community Services Universitas Muhammadiyah Palangkaraya

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.33084/jmd.v2i1.3450

Abstract

Lymphatic filariasis and onchocerciasis are two common filarial diseases caused by a group of parasitic nematodes called filarial worms, which co-habit with the bacteria organism Wolbachia. One good treatment approach seeks Wolbachia as a drug target. Here, a computer-aided molecular docking screening was conducted on a series of 52 pleuromutilin analogs against four Wolbachia enzymes: α-DsbA1 (PDB: 3F4R), α-DsbA2 (6EEZ), OTU deubiquitinase (6W9O), and cytoplasmic incompatibility factor CidA (7ESX) to find a more potent drug candidate(s) for the treatment of filarial diseases. The docking investigation was performed using the iGEMDOCK tool, while NAMD was utilized for the Molecular Dynamic (MD) simulation. The results of the virtual screening identified four ligand-protein interaction pairs with the highest binding affinities in the order: 17_6W9O (-117.31 kcal/mol) > 28_6EEZ (-104.43 kcal/mol) > 17_7ESX (-102.56 kcal/mol) > 41_7ESX (-101.51 kcal/mol), greater than that of the reference drug doxycycline_7ESX (-92.15 kcal/mol). These molecules (17, 28, and 41) showed excellent binding interactions, making very close contact with the receptors’ amino acid residues. They also showed better pharmacokinetic properties than doxycycline because they showed high intestinal absorption, were orally bioavailable and showed no AMES toxicity. Also, the stability of 17_6W9O interactions was confirmed by the MD simulation. Therefore, the selected molecules could be developed as potential drug candidates for treating filarial diseases.
Molecular Docking Investigation, Pharmacokinetic Analysis, and Molecular Dynamic Simulation of Some Benzoxaborole-Benzimidazole Hybrids: An Approach to Identifying Superior Onchocerca Inhibitors Fabian Audu Ugbe; Gideon Adamu Shallangwa; Adamu Uzairu; Ibrahim Abdulkadir
Borneo Journal of Pharmacy Vol. 6 No. 1 (2023): Borneo Journal of Pharmacy
Publisher : Institute for Research and Community Services Universitas Muhammadiyah Palangkaraya

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.33084/bjop.v6i1.3876

Abstract

Onchocerciasis is one of the major neglected tropical diseases caused by the filarial worm (Onchocerca volvulus), affecting an estimated population of about 37 million people living predominantly in tropical Africa. The major treatment approach has been based on the use of Ivermectin, which kills the microfilariae or the less effective Doxycycline targeting Wolbachia, endosymbiont of filarial nematodes. Flubendazole (FBZ) has proved effective in treating adult worms but with threatening adverse effects. Against this backdrop, therefore, a combined molecular docking study and pharmacokinetic screening were conducted on a series of benzimidazole-benzoxaborole hybrids to find more potent analogs with attributes that address the limitations of existing therapies. All the nineteen analogs were found to possess better docking scores than the reference drug (FBZ, Moldock scores = -120.466 and -125.359). The results of pharmacokinetic testing suggest that four molecules (14, 16, 19, and 20) are orally bioavailable and showed better ADMET properties than FBZ. These molecules and FBZ showed good binding interactions with the receptors’ active sites. Also, the molecular dynamic simulation performed on the docked complexes of 20 and FBZ confirmed the rigidity and stability of their interactions. Based on the results of this study, the selected molecules (especially 20) could be considered superior drug candidates for the treatment of Onchocerciasis.
In-Silico Design and Evaluation of the Anti-Wolbachia Potential of Boron-Pleuromutilins Fabian Audu Ugbe; Gideon Adamu Shallangwa; Adamu Uzairu; Ibrahim Abdulkadir
Borneo Journal of Pharmacy Vol. 6 No. 2 (2023): Borneo Journal of Pharmacy
Publisher : Institute for Research and Community Services Universitas Muhammadiyah Palangkaraya

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.33084/bjop.v6i2.4677

Abstract

Filariasis (Lymphatic filariasis and Onchocerciasis) is a common neglected tropical disease caused by parasitic nematodes called filarial worms, which often host the Wolbachia bacteria. A good treatment approach seeks Wolbachia as a drug target. Here, a computer-aided design of some boron-pleuromutilin analogs was conducted using the ligand-based drug design approach while performing molecular docking investigation and pharmacokinetics analyses to evaluate their drug-likeness properties. The newly designed compounds (49a, 49b, and 49c) showed improved inhibitory activities (pEC50) over those of the template and the clinically relevant pleuromutilins (retapamulin and lefamulin) in the order; 49b (pEC50 = 9.0409) > 49c (8.8175) > 49a (8.5930) > template (49) (8.4222) > retapamulin (6.7403) > lefamulin (6.1369). Standard docking performed with OTU deubiquitinase (6W9O) revealed the order of binding energies; 49c (-88.07 kcal/mol) > 49b (-84.26 kcal/mol) > doxycycline (-83.70 kcal/mol) > template (-82.57 kcal/mol) > 49a (-78.43 kcal/mol) > lefamulin (-76.83 kcal/mol) > retapamulin (-76.78 kcal/mol), with the new compounds all showing good pharmacological interactions with the receptor’s amino acids. The new analogs were also predicted to be orally bioavailable with better pharmacokinetic profiles than the template, retapamulin, lefamulin, and doxycycline having no more than one violation of Lipinski’s ROF. Therefore, the newly designed compounds could be considered potential anti-filarial drug candidates.
Co-Authors Adamu Uzairu Gideon Adamu Shallangwa Ibrahim Abdulkadir