Browsing by Author "Sakyi, P.O."
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Item Docking and Molecular Dynamics Identify Leads against 5 Alpha Reductase 2 for Benign Prostate Hyperplasia Treatment(Journal of Chemistry, 2023) Saah, S.A.; Sakyi, P.O.; Ayittey, K.; et al.Steroid 5 alpha-reductase 2 (5αR-2) is a membrane-embedded protein that together with other isoforms plays a key role in the metabolism of steroids. Tis enzyme catalyzes the reduction of testosterone to the more potent ligand, dihydrotestosterone (DHT) in the prostate. Androgens, testosterone, and DHT play important roles in prostate growth, development, and function. At the same time, both testosterone and DHT have been implicated in the pathogenesis of benign prostate hyperplasia (BPH). Inhibition of the DHTformation, therefore, provides a therapeutic strategy that ofers the possibility of preventing, delaying, or treating BPH. Currently, two steroidal drugs that inhibit 5αR-2, dutasteride and fnasteride, have been approved for clinical use. Tese two come at a high cost and also portray undesirable sexual side efects which necessitate the need to fnd new chemotherapeutic alternatives for the disease. Based on the aforementioned, fnasteride and dutasteride were subjected to scafold hopping, fragment-based de novo design, molecular docking, and molecular dynamics simulations employing databases like ChEMBL, DrugBank, PubChem, ChemSpider, and Zinc15 in the identifcation of potential hits targeting 5αR-2. Altogether, ten novel compounds targeting 5αR-2 were identifed with binding energies lower or comparable to fnasteride and dutasteride, the main inhibitors for this target. Molecular docking and molecular dynamics simulations studies identify amino acid residues Glu57, Phe219, Phe223, and Leu224 to be critical for ligand binding and complex stability. Te physicochemical and pharmacological profling suggests the potential of the hit compounds to be drug-like and orally active. Similarly, the quality parameter assessments revealed the hits possess LELP greater than 3 implying their promise as lead-like molecules. Te compounds A5, A9, and A10 were, respectively, predicted to treat prostate disorders with Pa (0.188, 0.361, and 0.270) and Pi (0.176, 0.050, and 0.093), while A8 and A9 were found to be associated with BPH treatment with Pa (0.09 and 0.127) and Pi (0.077 and 0.033), respectively. Structural similarity searches via DrugBank identifed the drugs faropenem, acemetacin, estradiol valerate, and yohimbine to be useful for BPH treatment suggesting the de novo designed ligands as potential chemotherapeutic agents for treating this disease.Item In Silico Discovery of Potential Inhibitors Targeting the RNA Binding Loop of ADAR2 and 5-HT2CR from Traditional Chinese Natural Compounds(Int. J. Mol. Sci., 2023) Broni, E.; Ashley, C.; Sakyi, P.O.; et al.Adenosine deaminase acting on RNA 2 (ADAR2) is an important enzyme involved in RNA editing processes, particularly in the conversion of adenosine to inosine in RNA molecules. Dysregulation of ADAR2 activity has been implicated in various diseases, including neurological disorders (including schizophrenia), inflammatory disorders, viral infections, and cancers. Therefore, targeting ADAR2 with small molecules presents a promising therapeutic strategy for modulating RNA editing and potentially treating associated pathologies. However, there are limited compounds that effectively inhibit ADAR2 reactions. This study therefore employed computational approaches to virtually screen natural compounds from the traditional Chinese medicine (TCM) library. The shortlisted compounds demonstrated a stronger binding affinity to the ADAR2 (<−9.5 kcal/mol) than the known inhibitor, 8-azanebularine (−6.8 kcal/mol). The topmost compounds were also observed to possess high binding affinity towards 5-HT2CR with binding energies ranging from −7.8 to −12.9 kcal/mol. Further subjecting the top ADAR2–ligand complexes to molecular dynamics simulations and molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) calculations revealed that five potential hit compounds comprising ZINC000014637370, ZINC000085593577, ZINC000042890265, ZINC000039183320, and ZINC000101100339 had favorable binding free energies of −174.911, −137.369, −117.236, −67.023, and −64.913 kJ/mol, respectively, with the human ADAR2 protein. Residues Lys350, Cys377, Glu396, Cys451, Arg455, Ser486, Gln488, and Arg510 were also predicted to be crucial in ligand recognition and binding. This finding will provide valuable insights into the molecular interactions between ADAR2 and small molecules, aiding in the design of future ADAR2 inhibitors with potential therapeutic applications. The potential lead compounds were also profiled to have insignificant toxicities. A structural similarity search via DrugBank revealed that ZINC000039183320 and ZINC000014637370 were similar to naringin and naringenin, which are known adenosine deaminase (ADA) inhibitors. These potential novel ADAR2 inhibitors identified herein may be beneficial in treating several neurological disorders, cancers, viral infections, and inflammatory disorders caused by ADAR2 after experimental validationItem In Silico Discovery of Potential Inhibitors Targeting the RNA Binding Loop of ADAR2 and 5-HT2CR from Traditional Chinese Natural Compounds(International Journal o f Molecular Sciences, 2023) Broni, E.; Ashley, C.; Sakyi, P.O.; et alAdenosine deaminase acting on RNA 2 (ADAR2) is an important enzyme involved in RNA editing processes, particularly in the conversion of adenosine to inosine in RNA molecules. Dysregulation of ADAR2 activity has been implicated in various diseases, including neurological disorders (including schizophrenia), inflammatory disorders, viral infections, and cancers. Therefore, targeting ADAR2 with small molecules presents a promising therapeutic strategy for modulating RNA editing and potentially treating associated pathologies. However, there are limited compounds that effectively inhibit ADAR2 reactions. This study therefore employed computational approaches to virtually screen natural compounds from the traditional Chinese medicine (TCM) library. The shortlisted compounds demonstrated a stronger binding affinity to the ADAR2 (<9.5 kcal/mol) than the known inhibitor, 8-azanebularine (6.8 kcal/mol). The topmost compounds were also observed to possess high binding affinity towards 5-HT2CR with binding energies ranging from 7.8 to 12.9 kcal/mol. Further subjecting the top ADAR2–ligand complexes to molecular dynamics simulations and molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) calculations revealed that five potential hit compounds comprising ZINC000014637370, ZINC000085593577, ZINC000042890265, ZINC000039183320, and ZINC000101100339 had favorable binding free energies of 174.911, 137.369, 117.236, 67.023, and 64.913 kJ/mol, respectively, with the human ADAR2 protein. Residues Lys350, Cys377, Glu396, Cys451, Arg455, Ser486, Gln488, and Arg510 were also predicted to be crucial in ligand recognition and binding. This finding will provide valuable insights into the molecular interactions between ADAR2 and small molecules, aiding in the design of future ADAR2 inhibitors with potential therapeutic applications. The potential lead compounds were also profiled to have insignificant toxicities. A structural similarity search via DrugBank revealed that ZINC000039183320 and ZINC000014637370 were similar to naringin and naringenin, which are known adenosine deaminase (ADA) inhibitors. These potential novel ADAR2 inhibitors identified herein may be beneficial in treating several neurological disorders, cancers, viral infections, and inflammatory disorders caused by ADAR2 after experimental validation.Item Inhibiting Leishmania donovani Sterol Methyltransferase to Identify Lead Compounds Using Molecular Modelling(Pharmaceuticals, 2023) Sakyi, P.O.; Kwofie, S.K.; Tuekpe, J.K.; et al.The recent outlook of leishmaniasis as a global public health concern coupled with the reportage of resistance and lack of efficacy of most antileishmanial drugs calls for a concerted effort to find new leads. The study combined In silico and in vitro approaches to identify novel potential synthetic small-molecule inhibitors targeting the Leishmania donovani sterol methyltransferase (LdSMT). The LdSMT enzyme in the ergosterol biosynthetic pathway is required for the parasite’s membrane fluidity, distribution of membrane proteins, and control of the cell cycle. The lack of LdSMT homologue in the human host and its conserved nature among all Leishmania parasites makes it a viable target for future antileishmanial drugs. Initially, six known inhibitors of LdSMT with IC50 < 10 µM were used to generate a pharmacophore model with a score of 0.9144 using LigandScout. The validated model was used to screen a synthetic library of 95,630 compounds obtained from InterBioScreen limited. Twenty compounds with pharmacophore fit scores above 50 were docked against the modelled three-dimensional structure of LdSMT using AutoDock Vina. Consequently, nine compounds with binding energies ranging from −7.5 to −8.7 kcal/mol were identified as potential hit molecules. Three compounds comprising STOCK6S-06707, STOCK6S-84928, and STOCK6S-65920 with respective binding energies of −8.7, −8.2, and −8.0 kcal/mol, lower than 22,26-azasterol (−7.6 kcal/mol), a known LdSMT inhibitor, were selected as plausible lead molecules. Molecular dynamics simulation studies and molecular mechanics Poisson–Boltzmann surface area calculations showed that the residues Asp25 and Trp208 were critical for ligand binding. The compounds were also predicted to have antileishmanial activity with reasonable pharmacological and toxicity profiles. When the antileishmanial activity of the three hits was evaluated in vitro against the promastigotes of L. donovani, mean half-maximal inhibitory concentrations (IC50) of 21.9 ± 1.5 µM (STOCK6S-06707), 23.5 ± 1.1 µM (STOCK6S-84928), and 118.3 ± 5.8 µM (STOCK6S-65920) were obtained. Furthermore, STOCK6S-84928 and STOCK6S-65920 inhibited the growth of Trypanosoma brucei, with IC50 of 14.3 ± 2.0 µM and 18.1 ± 1.4 µM, respectively. The identified compounds could be optimised to develop potent antileishmanial therapeutic agents.Item The Search for Putative Hits in Combating Leishmaniasis: The Contributions of Natural Products Over the Last Decade(Natural Products and Bioprospecting, 2021) Sakyi, P.O.; Devine, R.N.O.A.; Amewu, R.K.; Miller, W.A.; Kwofie, S.K.; Ismaila, E.Despite advancements in the areas of omics and chemoinformatics, potent novel biotherapeutic molecules with new modes of actions are needed for leishmaniasis. The socioeconomic burden of leishmaniasis remains alarming in endemic regions. Currently, reports from existing endemic areas such as Nepal, Iran, Brazil, India, Sudan and Afghanistan, as well as newly affected countries such as Peru, Bolivia and Somalia indicate concerns of chemoresistance to the classical antimonial treatment. As a result, effective antileishmanial agents which are safe and affordable are urgently needed. Natural products from both flora and fauna have contributed immensely to chemotherapeutics and serve as vital sources of new chemical agents. This review focuses on a systematic cross-sectional view of all characterized anti-leishmanial compounds from natural sources over the last decade. Furthermore, IC50/ EC50, cytotoxicity and suggested mechanisms of action of some of these natural products are provided. The natural product classification includes alkaloids, terpenes, terpenoids, and phenolics. The plethora of reported mechanisms involve calcium channel inhibition, immunomodulation and apoptosis. Making available enriched data pertaining to bioactivity and mechanisms of natural products complement current efforts geared towards unraveling potent leishmanicides of therapeutic relevance.Item Synthetic and Naturally Occurring Heterocyclic Anticancer Compounds with Multiple Biological Targets(MDPI, 2021) Osei-Safo, D.; Amewu, R.K.; Sakyi, P.O.; et al.Abstract: Cancer is a complex group of diseases initiated by abnormal cell division with the potential of spreading to other parts of the body. The advancement in the discoveries of omics and bio- and cheminformatics has led to the identification of drugs inhibiting putative targets including vascular endothelial growth factor (VEGF) family receptors, fibroblast growth factors (FGF), platelet derived growth factors (PDGF), epidermal growth factor (EGF), thymidine phosphorylase (TP), and neuropeptide Y4 (NY4), amongst others. Drug resistance, systemic toxicity, and drug ineffectiveness for various cancer chemo-treatments are widespread. Due to this, efficient therapeutic agents targeting two or more of the putative targets in different cancer cells are proposed as cutting edge treatments. Heterocyclic compounds, both synthetic and natural products, have, however, contributed immensely to chemotherapeutics for treatments of various diseases, but little is known about such compounds and their multimodal anticancer properties. A compendium of heterocyclic synthetic and natural product multitarget anticancer compounds, their IC50, and biological targets of inhibition are therefore presented in this review.Item Targeting Leishmania donovani sterol methyltransferase for leads using pharmacophore modeling and computational molecular mechanics studies(Informatics in Medicine Unlocked, 2023) Sakyi, P.O.; Broni, E.; Amewu, R.K.; Miller III, W.A.; Wilson, M.D.; Kwofie, S.K.The mortalities and morbidities of leishmaniasis are high and the disease is under reported globally. The absence of vaccines coupled with chemotherapeutic challenges including chemoresistance, scarcity and toxicity have made the fight against leishmaniasis an arduous one. Furthermore, the treatment options currently available for leishmaniasis are long and sometimes require hospitalization. There is therefore the need to explore novel pathways to identify new compounds with alternative mechanisms of action. A pharmacophore-based screening was employed in identifying new potential inhibitors with unique scaffolds targeting Leishmania donovani sterol methyltransferase (LdSMT), a key enzyme for ergosterol biosynthesis. To accomplish this, 22,26-azasterol, a known inhibitor of this target and five other derivatives with IC50 less than 10 μM were used to generate a robust 3D pharmacophore model via LigandScout with a score of 0.9144. The validated model was used as a query to screen a library of 69034 natural products obtained from the InterBioScreen Limited. Compounds with pharmacophore fit scores above 50 were docked against the modelled structure of LdSMT. Altogether, ten molecules with binding energies between − 7 and − 11 kcal/mol were identified as potential bioactive molecules. The molecular dynamics simulation and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations reinforced the results from the docking studies suggesting the selected hits bind effectively at the active sites of the target protein. The compounds were observed to bind in the S-adenosine-L-homocysteine binding pocket of the modelled LdSMT with Trp208 and Val330 predicted as key residues critical for ligand binding. Prediction of biological activity with probability of activity (Pa) greater than probability of inactivity (Pi) revealed that seven compounds (STOCKIN-54848, STOCKIN-89115, STOCKIN-68720, STOCKIN-44724, STOCKIN-76694, STOCKIN-47277 and STOCKIN-95708) possessed antileishmanial properties. STOCKIN-89115, STOCKIN-68720, STOCKIN-44724, and STOCKIN-47277 were predicted to be membrane perme ability inhibitors, while all ten hit compounds possessed antineoplastic activity. The compounds have the propensity of disrupting ergosterol biosynthesis leading to the suppression of growth in Leishmania donovani. The compounds were predicted to have good absorption, distribution, metabolism, excretion and toxicity profiles, hence their potential antileishmanial activity can be exploited upon experimental corroboration.