Browsing by Author "Faizan, M."

Now showing 1 - 3 of 3

Identification of plant based anti-diabetic drug leads: A computer-based drug discovery approach
(Department of Social Statistics, Faculty of Social Sciences, University of Kelaniya Sri Lanka, 2023) Katipearachchi, S. H.; Faizan, M.; Kalansuriya, P.; Attanayake, A. P.
Diabetes mellitus is known to be one of the fastest-rising chronic metabolic diseases with multiple etiologies. The disease is characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action or both. Available therapeutic agents, come with their fair share of side effects. Plant-derived medications that have been used for centuries in the treatment of diabetes in ayurveda and folk medicine have gained a lot of attention in recent years. Studies have shown that plants consist of many bioactive compounds with anti-diabetic properties. Computer-aided drug discovery is slowly gaining popularity with molecular docking accelerating drug discovery by providing structure-based interactions between ligand and receptor proteins. This study was designed to use computational methods to identify the best anti-diabetic compounds devised from ten selected plants. A total of ten plants and three target receptor proteins were selected for in silico screening based on the literature. The selected plants were Nigella sativa L., Coccinia grandis (L.) Voigt, Cheilocostus speciosus (J.Koenig) C.D.Specht, Momordica charantia L., Strychnos potatorum L.f, Gymnema sylvestre (Retz.) R.Br., Aloe vera (L.) Burm.f., Scoparia dulcis L., Abutilon indicum (L.) Sweet, and Trigonella foenum-graceum L. A phytochemical compound library with a total of 952 ligands was prepared using IMPPAT database. The main target receptor proteins, include 􀁄-glucosidase, 􀁄-amylase and dipeptidyl peptidase-IV (DPP-IV), based on their key roles in the maintenance of glucose homeostasis. The 3D protein structures were downloaded from the RCSB Protein Data Bank. Miglitol, sitagliptin and acarbose were selected as reference drugs for each target protein to conduct a comparative study. Biovia Discovery Studio was used to visualize the target protein and prepare the protein for virtual screening. UCSF Chimera and PyRx Autodock were used for the energy minimization of the proteins and the virtual screening respectively. Schrodinger Maestro was used for the dynamic simulation studies with the OPLS- 2005 force field and TIP3P Solvent model. The compound library was screened by carrying out flexible docking against each target protein. The search space for virtual screening was defined to include all the critical inhibitor-binding sites based on the literature. All the compounds having binding affinity less than -6 kcal/mol were selected.. Only the compounds with promising binding energy values, depending on each target, were subjected to the target-ligand interaction analysis conducted using Biovia Discovery Studio. The binding affinity and interaction patterns of phytochemical ligands were evaluated against three receptor proteins. The best three molecules for each protein were selected based on the best hydrogen bond interactions since they determine the specific, energetically favorable ligand binding at the target sites. The selected 12 molecules were further analyzed for the best target-ligand binding conformation and subjected to molecular dynamics simulation. Compound 27 and compound 85 in T. foenum-graceum with RMSD less than 3Å and hydrogen bond retention above 75% in 100NS simulation were identified as promising therapeutic drug leads for the treatment of diabetes. In vitro screening for the antidiabetic activities would be conducted using 􀁄-glucosidase, 􀁄-amylase and DPP-IV assays to further assess their effectiveness as anti-diabetic drug leads.
In silico identification and in vitro validation of alpha-hederin as a potent inhibitor of Wnt/β-catenin signaling pathway in breast cancer stem cells.
(Springer-Verlag, GmbH, 2024) Saliu, T.P.; Seneviratne, N.N.; Faizan, M.; Rajagopalan, U.; Perera, D.C.; Adhikari, A.; Senathilake, K.S.; Galhena, P.B.; Tennekoon, K.H.; Samarakoon, S.R.
Cancer stem cells (CSCs) play a vital role in metastasis, recurrence and chemoresistance in breast cancer. β-catenin, which is a frequently over activated protein in CSCs, binds to T-cell factor/lymphoid enhancer factor (Tcf/Lef) family transcription factors leading to ectopic expression of Wnt pathway responsive genes necessary for the maintenance and action of CSCs. With the aim of identifying a small molecules that can effectively eliminate CSCs, molecular docking studies were performed against the Tcf/Lef binding hotspot on β-catenin using a library of 100 natural or synthetic small molecules. Small molecule ligands giving docking energy better than - 7 kcal/mol were further investigated by binding interactions analysis and molecular dynamics (MD) simulations. These compounds were then investigated in vitro, for cytotoxicity against CSCs isolated from MDA-MB-231 triple negative breast cancer cells. Alpha-hederin (AH) was identified as the only compound in the selected library that has cytotoxicity against breast CSCs. AH was further investigated for it's ability to regulate Wnt pathway target genes (Cyclin D1 and CD44)and the tumor suppressor p53by real-time quantitative PCR. Absorption, distribution, metabolism, excretion and toxicity properties of the AH was predicted in silico. AH significantly down regulated the transcription of Cyclin D1 and CD44 while up-regulating the transcription of p53. AH was predicted to have acceptable drug likeness. Although AH is currently known to inhibit the growth of various cancer cells in vitro, present study demonstrated for the first time that it is a potent inhibitor of Wnt/β-catenin signaling pathway and induce apoptosis in breast CSCs.
Mutational analysis of driver and non-driver mutations of Philadelphia chromosome-negative myeloproliferative neoplasms;diagnosis and recent advances in treatment
(Science Publications, 2024) Afolabi, B.O.; Riwaz, A.; Weerasena, J.; Williams, S.; Denipitiya, T.; Somawardana, B.; Faizan, M.; Galhena, B.P.
Myeloproliferative neoplasms (MPNs) are hematological disorders affecting myeloid stem cells. They are classified as Philadelphia (Ph) chromosome positive-chronic myeloid leukemia, and Ph-negative polycythemia vera, essential thrombocythemia, primary myelofibrosis, chronic neutrophilic leukemia, chronic eosinophilic leukemia, juvenile myelomonocytic leukemia, and MPN unclassifiable. This review is mainly focused on the Ph-negative MPNs namely, PV, ET, and PMF. These affect both males and females with a slight male predominance, with patients mainly presenting in the seventh decade. Patients often present with thrombotic events resulting in complications that lower survival rates. The major driver mutations that have been identified in MPNs are JAK2 Exon 14, JAK2 Exon 12, MPL Exon 10, and CALR Exon 9. The importance of these driver mutations gives due recognition to their inclusion into the 2022 diagnostic criteria of the MPN WHO Classification. However, other non-driver mutations have also been reported, especially in triple-negative cases. These mutations lead to downstream constitutive activation of the JAK/STAT signaling pathway, as well as the MAPK, and PI3K/Akt pathways. Insights into the molecular pathogenesis of MPN and its association with JAK2, CALR, and MPL mutations have identified JAK2 as a rational therapeutic target. Thus, as an approach to MPN therapy, JAK2 inhibitors, such as ruxolitinib, have been shown to effectively inhibit JAK2, and are currently in clinical trials in combination with other drug classes. This review comprehensively examines the molecular markers of the main Ph-negative MPNs, as well as diagnosis and treatment options.