Computational identification of potential modulators of heme-regulated inhibitor (HRI) for pharmacological intervention against sickle cell disease.

Sickle cell disease (SCD) poses a significant health challenge and therapeutic approaches often target fetal hemoglobin (HbF) to ameliorate symptoms. Hydroxyurea, a current therapeutic option for SCD, has shown efficacy in increasing HbF levels. However, concerns about myelosuppression and thrombocytopenia necessitate the exploration of alternative compounds. Heme-regulated inhibitor (HRI) presents a promising target for pharmacological intervention in SCD due to its association with HbF modulation. This study screened compounds for their potential inhibitory functions against HRI. Small-molecule compounds from 17 folkloric plants were subjected to in silico screening against HRI. Molecular docking was performed, and free binding energy calculations were determined using molecular mechanics with generalized born and surface area (MMGBSA). Lead compounds were subjected to molecular dynamics simulation at 100 ns. Computational quantum mechanical modeling of the lead compounds was subsequently performed. We further examined the pharmacodynamics, pharmacokinetic and physiological properties of the identified compounds. Five potential HRI inhibitors, including kaempferol-3-(2G-glucosyrutinoside), epigallocatechin gallate, tiliroside, myricetin-3-O-glucoside and cannabiscitrin, with respective docking scores of -16.0, -12.17, -11.37, -11.56 and 11.07 kcal/mol, were identified. The MMGBSA analysis of the complexes yielded free-binding energies of -69.76, -71.17, -60.44, -53.55 and -55 kcal/mol, respectively. The identified leads were stable within HRI binding pocket for the duration of the 100 ns simulation. The study identified five phytoligands with potential inhibitory effects on HRI. This finding holds promise for advancing SCD treatment strategies. However, additional preclinical analyses are warranted to validate the chemotherapeutic properties of the lead compounds.Communicated by Ramaswamy H. Sarma.

Identification of levomenthol derivatives as potential dipeptidyl peptidase-4 inhibitors: a comparative study with gliptins.

Dipeptidyl peptidase-4 (DPP4) inhibitors are a potent therapeutic treatment for type 2 diabetes mellitus (T2DM). There is a family of compounds used as DPP4 inhibitors (DPP4Is) called gliptins. They bind tightly to DPP4 to form an inactive protein-ligand complex. However, there remains a need to identify novel DPP4Is that are more efficacious and safer due to the increasing prevalence of T2DM and the undesirable side effects of gliptins. To identify potential DPP4Is, we screened over 1800 novel compounds in a comparative study with gliptins. We performed dual-factor molecular docking to assess the binding affinity of the compounds to DPP4 and found four compounds with a higher binding affinity to DPP4 than currently used gliptins. The newly identified compounds interacted with the dyad glutamate (GLU205 and GLU206) and tyrosine (TYR662 and TYR666) residues in DPP4's active site. We performed molecular dynamics simulations to determine the stability of the protein-ligand complexes formed by the compounds and DPP4. Furthermore, we examined the toxicity and pharmacological profile of the compounds. The compounds are drug-like, easy to synthesize, and relatively less toxic than gliptins. Collectively, our results suggest that the novel compounds are potential DPP4Is and should be considered for further studies to develop novel antidiabetics.Communicated by Ramaswamy H. Sarma.

Potential Inhibitory Biomolecular Interactions of Natural Compounds With Different Molecular Targets of Diabetes.

Type II diabetes is an endemic disease and is responsible for approximately 90% to 95% of diabetes cases. The pathophysiological distortions are majorly ß-cell dysfunction, insulin resistance, and long-term inflammation, which all progressively unsettle the control of blood glucose levels and trigger microvascular and macrovascular complications. The diverse pathological disruptions which patients with type II diabetes mellitus exhibit precipitate the opinion that different antidiabetic agents, administered in combination, might be required to curb this menace and maintain normal blood glucose. To this end, natural compounds were screened to identify small molecular weight compounds with inhibitory effects on protein tyrosine phosphatase 1B (PTP1B), dipeptidyl-peptidase-4 (DPP-4), and α-amylase. From the result, the top 5 anthocyanins with the highest binding affinity are reported herein. Further ADMET profiling showed moderate pharmacokinetic profiles for these compounds as well as insignificant toxicity. Cyanidin 3-(p-coumaroyl)-diglucoside-5-glucoside (-15.272 kcal/mol), cyanidin 3-O-(6"-malonyl-3"-glucosyl-glucoside) (-9.691 kcal/mol), and delphinidin 3,5-O-diglucoside (-12.36 kcal/mol) had the highest binding affinities to PTP1B, DPP-4, and α-amylase, respectively, and can be used in combination to control glucose fluctuations. However, validations must be carried out through further in vitro and in vivo tests.

Computational identification of potential modulators of heme-regulated inhibitor (HRI) for pharmacological intervention against sickle cell disease.

Background: Sickle cell disease (SCD) poses a significant health challenge and therapeutic approaches often target fetal hemoglobin (HbF) to ameliorate symptoms. Hydroxyurea, a current therapeutic option for SCD, has shown efficacy in increasing HbF levels. However, concerns about myelosuppression and thrombocytopenia necessitate the exploration of alternative compounds. Heme-regulated inhibitor (HRI) presents a promising target for pharmacological intervention in SCD due to its association with HbF modulation. This study systematically screened compounds for their potential inhibitory functions against HRI. Methods: Small-molecule compounds from 17 plants commonly utilized in traditional SCD management were subjected to in silico screening against HRI. Molecular docking was performed, and free binding energy calculations were determined using molecular mechanics with generalized born and surface area (MMGBSA). The lead compounds were subjected to molecular dynamics simulation at 100 ns. Computational quantum mechanical modelling of the lead compounds was subsequently performed. We further examined the pharmacodynamics, pharmacokinetic and physiological properties of the identified compounds. Results: Five potential HRI inhibitors, including kaempferol-3-(2G-glucosyrutinoside), epigallocatechin gallate, tiliroside, myricetin-3-O-glucoside, and cannabiscitrin, with respective docking scores of -16.0, -12.17, -11.37, -11.56 and 11.07 kcal/mol, were identified. The MMGBSA analysis of the complexes yielded free-binding energies of -69.76, -71.17, -60.44, 53.55, and - 55 kcal/mol, respectively. The identified leads were stable within HRI binding pocket for the duration of 100 ns simulation. Conclusions: The study successfully identified five phytoligands with potential inhibitory effects on HRI, opening avenues for their use as modulators of HbF in SCD patients. This finding holds promise for advancing treatment strategies in SCD. However, additional preclinical analyses are warranted to validate the chemotherapeutic properties of the lead compounds.

Discovery of Promising Inhibitors of Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), Estrogen Receptor (ER), and Phosphatidylinositol-3-kinase a (PI3Ka) for Personalized Breast Cancer Treatment.

Despite the rapid developments and advancements to improve treatments, Breast cancer remains one of the deadliest health challenges and the most frequently diagnosed tumor. One of the major problems with treatment is the unique difference that each cancerous cell exhibits. As a result, treatment of breast cancer has now become more personalized based on the specific features of the tumor such as overexpression of growth factor receptors (Epidermal growth factor receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2)), hormone receptors (Human Estrogen receptor alpha (ER)) and kinases involved in pivotal signaling associated with growth (Phosphatidylinositol 3-kinase (PI3K)). Several chemotherapeutic agents have been developed to curb the menace, but the associated adverse drug effects cannot be overlooked. To this end, this study employed a molecular modeling approach to identify novel compounds of natural origin that can potentially antagonize the receptors (mentioned above) associated with the pathophysiology of breast cancer and at the same time pose very little or no side effects. The results of the molecular model of biological interactions between a library of 118 anthocyanins and the binding pockets of the protein targets identified 5 compounds (Pelargonin, Delphinidin 3-O-rutinoside, Malvin, Cyanidin-3-(6-acetylglucoside), and Peonidin 3-O-rutinoside) with good binding affinities to the protein targets. Further MM-GBSA calculations returned high binding energies. The specific molecular interactions between the compounds and the targets were analyzed and reported herein. Also, all the compounds exhibited good pharmacokinetic profiles and are therefore recommended for further analyses as they could be explored as new treatment options for a broad range and personalized breast cancer treatments.

Molecular Modeling Studies of Natural Inhibitors of Androgen Signaling in Prostate Cancer.

Prostate cancer is the second most common disease in men and the sixth leading cause of death from cancer globally, with 20 million men expected to be affected by 2024 thus considered as chronic illness which requires immediate attention. As an androgen-dependent illness that relies on the androgen receptor for development and progression, inhibition of the androgen receptor can lead to a therapeutic solution, hence serving as a vital therapeutic target. This study focused on the computational analysis of the inhibitory potentials of Vitis vinifera, a reported plant with anti-cancer properties, against androgen receptor employing molecular docking, ADMET studies, Binding energy study, pharmacophore modeling, and molecular dynamics simulation approaches. After the investigation, it was determined that 5 compounds: cis-piceid, cis-astrigin, gallocatechin, phlorizin, and trans-polydatin, might be possible androgen receptor inhibitors since they had higher docking scores and ADMET qualities than compared standards, with cis-piceid being the best-predicted inhibitor.

Structure-based discovery of selective CYP17A1 inhibitors for Castration-resistant prostate cancer treatment.

Prostate cancer (PCa) is the most common malignancy found in men and the second leading cause of cancer-related death worldwide. Castration-resistant PCa (CRPC) is defined by PCa cells that stop responding to hormone therapy. Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) plays a critical role in the biosynthesis of androgens in humans. Androgen signaling cascade is a principal survival pathway for PCa cells and androgen-deprivation therapy (ADT) remains the key treatment for patients marked with locally advanced and metastatic PCa cells. Available synthetic drugs have been reported for toxicity, drug resistance, and decreasing efficacy. Thus, the design of novel selective inhibitors of CYP17A1 lyase would help circumvent associated side effects and improve pharmacological activities. Therefore, we employed structural bioinformatics techniques via molecular docking; molecular mechanics generalized born surface area (MM-GBSA), molecular dynamics (MD) simulation, and pharmacokinetic study to identify putative CYP17A1 lyase inhibitors. The results of the computational investigation showed that the Prunus dulcis compounds exhibited higher binding energy than the clinically approved abiraterone acetate. The stability of the ligand with the highest binding affinity (quercetin-3-o-rutinoside) was observed during MD simulation for 10 ns. Quercetin-3-o-rutinoside was observed to be stable within the active site of CYP17A1Lyase throughout the simulation period. The result of the pharmacokinetic study revealed that these compounds are promising therapeutic agents. Collectively, this study proposed that bioactive compounds from P. dulcis may be potential selective inhibitors of CYP17A1Lyase in CRPC treatments.