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Current Topics in Medicinal Chemistry - Online First
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Identification of Novel Tyrosinase Inhibitors with Nanomolar Potency Using Virtual Screening Approaches
Authors: Guohong Liu, Shihao Liu, Tegexibaiyin Wang and Xiaofang LiAvailable online: 02 October 2024More LessIntroductionHyperpigmentation disorders are caused by excess production of the pigment melanin, catalyzed by the enzyme tyrosinase. Novel tyrosinase inhibitors are needed as therapeutic agents to treat these conditions.
MethodTo discover new inhibitors, we performed a virtual screening of the ZINC20 library containing 1.4 billion compounds. An initial filter for drug-likeness, ADMET properties, and synthetic accessibility reduced the library to 10,217 hits. Quantitative structure-activity relationship (QSAR) modeling of this subset predicted nanomolar inhibitory potency for several chemical scaffolds. Comparative molecular docking studies and rigorous binding energy calculations further prioritized four cysteine-containing dipeptide compounds based on predicted strong binding affinity and mode to tyrosinase.
ResultsMicrosecond-long molecular dynamics simulations provided additional atomistic insights into the stability of inhibitor-enzyme binding interactions. This integrated computational workflow effectively sampled an extremely large chemical space to discover four novel tyrosinase inhibitors with half-maximal inhibitory concentration values below 10 nM.
ConclusionOverall, this demonstrates the power of virtual screening and multi-faceted computational techniques to accelerate the discovery of potent bioactive ligands from massive compound libraries by efficiently sampling chemical space.
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Protective Effects of Chitosan-Loaded Pomegranate Peel Extract Nanoparticles on Infertility in Diabetic Male Rats
Available online: 22 August 2024More LessBackgroundDiabetes Mellitus (DM) is known to have an impact on the health of the male reproductive system. It is linked to low sperm quality, increased oxidative stress, and an increased generation of reactive oxygen species in the seminal fluid. Pomegranate extract has phenolic compounds and significant protective properties against oxidative stress, male sex hormone disruptions, and sperm abnormalities.
ObjectiveThe current study aimed to evaluate the effectiveness of Pomegranate Peel Extract Nanoparticles (PPENPs) on male fertility in diabetic rats.
MethodsDM was induced in rats by intraperitoneal injection of streptozotocin (60 mg/kg). Twenty-four rats were divided into four groups, 6 rats in each group: control, DM, DM+empty NPs (60 mg/kg, orally), and DM+PPENPs (60 mg/kg, orally).
ResultsAdministration of PPENPs increased the levels of insulin, FSH, LH, testosterone, catalase, glutathione reduced, and semen fructose. PPENPs also improved sperm quality, as seen by improvements in sperm morphology, motility, count, and the ability of metabolically active spermatozoa to convert blue resazurin dye to pink resorufin. However, PPENPs decreased levels of glucose, malonaldehyde, nitric oxide, and sperm abnormalities. Also, histological investigation of the PPENPs showed improvement in testis tissue architecture and increased the diameter size of seminiferous tubules and germinative layer thickness.
ConclusionOur investigation proved that the treatment of PPENPs has a protective effect on the reproductive system of male diabetic rats, improving fertility parameters, healthy sperm profiles, and the antioxidant system.
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Unveiling the Potential of Bergenia Phenolics: Vitexin's Role in Allosteric Modulation of PBP2a as a Strategy against MRSA Resistance
Authors: Abhishek Kumar Verma, Anshulika Saxena and Sandeep Kumar SrivastavaAvailable online: 19 August 2024More LessBackgroundFor cell wall biosynthesis, drug-resistant S. aureus uses a special protein called PBP2a, even when antibiotics are present and stop its natural processes from working. To combat this, novel therapies are required to specifically target PBP2a with greater efficacy.
MethodsUsing computational approaches, we screened nine phenolic compounds from other Bergenia species, including Bergenia ciliata, Begenia ligulata, Bergenia purpurascens, and Bergenia stracheyi, against the PBP2a allosteric site to explore the potential interaction between phenolic compounds and a specific region of PBP2a known as the allosteric site.
ResultsBased on interaction patterns and estimated affinity, vitexin has been found to be the most prominent phenolic compound. We performed MD simulations on vitexin and ceftazidime as control molecules based on the docking results. The binding free energy estimates of vitexin
(-94.48 +/- 17.92 kJ/mol) using MM/PBSA were lower than those of the control (-67.61 +/- 12.29 kJ/mol), which suggests that vitexin may be able to inhibit PBP2a activity in MRSA.
ConclusionIt has been intriguing to observe a correlation between the affinity of the lead compounds at the allosteric site and the modification of Tyr446, the active site gatekeeper residue in PBP2a. Our findings have implied that lead compounds can either directly or indirectly decrease PBP2a activity by inducing allosteric site change in conventional medicine.
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