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Triterpenoids from Gymnema Sylvestre R.Br. (Periploca of the Woods): Biological Significance in the Treatment of Diabetes
Published in Megh R. Goyal, Preeti Birwal, Santosh K. Mishra, Phytochemicals and Medicinal Plants in Food Design, 2022
The use of bioinformatics resources namely databases information on diabetes, molecular modeling approaches, QSAR and softwares, have contributed in identification of novel “drug-like” molecules and the analysis of their pharmacokinetic properties (absorption, distribution, metabolism, excretion, and toxicity) [63, 64]. The study discussed the prediction of anti-diabetic activity of phytomolecules by QSAR model, a statistical approach in prediction of “drug-like” molecules. Molecular docking and ADMET analysis showed active Gymnemic acid analogs. However, poor bioavailability of molecules requires further optimization. The in silico screening methods provide an important tool to gain insights on the potential of natural “lead molecules” for drug designing in diabetes.
Granulation of Poorly Water-Soluble Drugs
Published in Dilip M. Parikh, Handbook of Pharmaceutical Granulation Technology, 2021
Albert W. Brzeczko, Firas El Saleh, Hibreniguss Terefe
Over the past several decades, advances in drug discovery techniques have been significant in identifying new and novel therapeutics agents in the pharmaceutical industry. Receptor mapping and molecular modeling coupled with high-throughput screening have revealed a plethora of drug candidates for numerous disease states. Because of the nature and the location of many of these receptors in a lipophilic membrane, drug candidates having the best molecular configuration and fitting into these receptors may, by design, be poorly water-soluble. It is estimated that 90% of new chemical entities in drug development are characterized as poorly water-soluble with a potential market impact projected at $145 billion [1]. Crestor® (rosuvastatin calcium), Nexium® (esomeprazole magnesium), and Sovaldi® (sofosbuvir) are drugs with significant therapeutic impact, which are classified as poorly water-soluble. This rise of more poorly water-soluble drug candidates in development presents a challenge to formulators of pharmaceutical oral solid dosage forms to improve the drug’s bioavailability while maintaining product stability, both physically and chemically, as well as providing a robust commercial process.
The Evolution of Anticancer Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Once the structure of a cancer-related protein has been established, its co-ordinates can be used to generate a computer-based three-dimensional model in one of the many molecular modeling software packages available (e.g., AMBERTM and DOCKTM), which can then be used for drug discovery purposes. For example, such a model can be used for in silico screening whereby large virtual libraries of molecules (including chemical company catalogs) can be searched in order to find examples of molecules that may interact and fit into various pockets and clefts of the protein. These molecules can then be obtained commercially or synthesized and used as leads for the development of novel inhibitors or agonists of the protein function. Alternatively, once the structure of a cancer-related protein is available, it can be produced in relatively large quantities (e.g., multi-milligram) using plasmid-transformed cell-based techniques and then used for screening against physical compound libraries (see Section 2.3.3).
Design and synthesis of novel quinazolinone-based derivatives as EGFR inhibitors with antitumor activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Amr Sonousi, Rasha A. Hassan, Eman O. Osman, Amr M. Abdou, Soha H. Emam
The crystallographic structure of EGFR protein (PDB: 1M17) was obtained from the protein data bank website, (http://www.pdb.org) with resolution of 2.60 Å. All the molecular modelling studies were carried out using Molecular Operating Environment (MOE 2020.09; Chemical Computing Group, Canada) as the computational software. The hydrogen atoms were added, the protonation states of the amino acid residues were assigned, and the partial charges of atoms were added using Protonate 3D algorithm. Compounds were modelled using MOE builder, and the structure was energy minimised using the MMFF94x force field. Using the MOE induced-fit Dock tool, docking studies of the synthesised compound into the active site was done and the final docked complexes of ligand–enzyme was selected according to the criteria of binding energy score combined with geometrical matching quality.
Novel oxindole/benzofuran hybrids as potential dual CDK2/GSK-3β inhibitors targeting breast cancer: design, synthesis, biological evaluation, and in silico studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Wagdy M. Eldehna, Sara T. Al-Rashood, Tarfah Al-Warhi, Razan O. Eskandrani, Amal Alharbi, Ahmed M. El Kerdawy
All the molecular modelling simulations were performed using Molecular Operating Environment (MOE, 2010.10) software. All minimizations were carried out with MOE until an RMSD gradient of 0.05 kcal·mol−1 Å−1 with MMFF94× force field and the partial charges were automatically calculated. The X-ray crystallographic structure of CDK2 co-crystallized with an oxindole derivative (IC50 = 60 nM) as inhibitor (PDB ID: 1FVT)109 and of GSK-3β co-crystallized with the oxindole derivative Indirubin-3′-monoxime (IC50 = 22 nM) as inhibitor (PDB ID: 1Q41)110 were downloaded from the protein data bank120. The selection of these two protein structures specifically attributed to their co-crystallization with potent CDK2 and GSK-3β oxindole-based inhibitors, respectively.
Modulatory role of rutin on 2,5-hexanedione-induced chromosomal and DNA damage in rats: validation of computational predictions
Published in Drug and Chemical Toxicology, 2020
Aliyu Muhammad, David Ebuka Arthur, Sanusi Babangida, Ochuko L. Erukainure, Ibrahim Malami, Hadiza Sani, Aliyu Waziri Abdulhamid, Idayat Omoyemi Ajiboye, Ahmed Ariyo Saka, Nafisa Muhammed Hamza, Suleiman Asema, Zaharaddeen Muhammad Ado, Taibat Ishaq Musa
The role of molecular modeling for computational predictions cannot be overemphasized. To this end, recently from our Laboratory we reported the role of molecular modeling strategies in validating the effects of chrysin on sodium arsenite-induced chromosomal and DNA damage (Babangida et al. 2018). From the study, we have been able to unravel the potency of chrysin against sodium arsenite-induced chromosomal and DNA damage, which was attributed to inhibition of SAM-dependent methyltransferase (Babangida et al. 2018). This has actually given us the impetus to use other flavonoids such as rutin (as in the case of current research) and 2,5-hexanedione, a metabolite of frequently used chemical (n-hexane) using in silico and in vivo models. Therefore, this study was primarily designed to evaluate the ameliorative, preventive, and curative effects of rutin on 2,5-hexanedione-induced oxidative, chromosomal, and DNA damage in vivo vis-à-vis the validation of computational predictions on the possible role of 2,5-hexanedione in causing damage to macromolecules (proteins and DNA) as well as the potential oral toxicities of rutin. Biochemically, the findings from this study will further underscore the anti-oxidative, DNA protective, and anticlastogenic properties of rutin against a metabolite of the so-called environmentally friendly chemical, 2,5-hexanedione. This will as well highlight the contribution of computational predictions in phytomedicine and toxicology research.