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.

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.

Molecular docking, simulation and binding free energy analysis of small molecules as PfHT1 inhibitors.

Antimalarial drug resistance has thrown a spanner in the works of malaria elimination. New drugs are required for ancillary support of existing malaria control efforts. Plasmodium falciparum requires host glucose for survival and proliferation. On this basis, P. falciparum hexose transporter 1 (PfHT1) protein involved in hexose permeation is considered a potential drug target. In this study, we tested the antimalarial activity of some compounds against PfHT1 using computational techniques. We performed high throughput virtual screening of 21,352 small-molecule compounds against PfHT1. The stability of the lead compound complexes was evaluated via molecular dynamics (MD) simulation for 100 nanoseconds. We also investigated the pharmacodynamic, pharmacokinetic and physiological characteristics of the compounds in accordance with Lipinksi rules for drug-likeness to bind and inhibit PfHT1. Molecular docking and free binding energy analyses were carried out using Molecular Mechanics with Generalized Born and Surface Area (MMGBSA) solvation to determine the selectivity of the hit compounds for PfHT1 over the human glucose transporter (hGLUT1) orthologue. Five important PfHT1 inhibitors were identified: Hyperoside (CID5281643); avicularin (CID5490064); sylibin (CID5213); harpagoside (CID5481542) and quercetagetin (CID5281680). The compounds formed intermolecular interaction with the binding pocket of the PfHT1 target via conserved amino acid residues (Val314, Gly183, Thr49, Asn52, Gly183, Ser315, Ser317, and Asn48). The MMGBSA analysis of the complexes yielded high free binding energies. Four (CID5281643, CID5490064, CID5213, and CID5481542) of the identified compounds were found to be stable within the PfHT1 binding pocket throughout the 100 nanoseconds simulation run time. The four compounds demonstrated higher affinity for PfHT1 than the human major glucose transporter (hGLUT1). This investigation demonstrates the inhibition potential of sylibin, hyperoside, harpagoside, and avicularin against PfHT1 receptor. Robust preclinical investigations are required to validate the chemotherapeutic properties of the identified compounds.