Computational and theoretical insights into the cytotoxic prospects of compounds isolated from against Leukemia.

The present study investigated the cytotoxic prospects of isolated compounds from against leukemia, using computational tools. Comprehensive literature searches revealed only buchaninoside, mutangin, methyl 3β-acetoxy-11α, 19α, 28-trihydroxyurs-12-en-23-oic acid, 3β, 11α, 19α-trihydroxyurs-12-en-23, 28-dioic acid, 3β-acetoxy-19α, 24, 28-trihydroxyurs-12-ene, 3-oxo-19α,28-dihydroxyurs-12-en-24-oic acid, and elabunin have been isolated from . The compounds were subjected to Density Functional Theory (DFT) and Molecular Dynamics (MD) analyses, with Fms-like tyrosine kinase (FLT3) and catalytic binding sites of Murine Leukemia Virus (MLV) as the target proteins in lukemia.

Potential molecular mechanisms underlying the ameliorative effect of Cola nitida (Vent.) Schott & Endl. on insulin resistance in rat skeletal muscles.

Ethnopharmacological Relevance: Cola nitida (Vent.) Schott & Endl. are among the common medicinal plants employed in traditional medicine for treating diabetes and its complications.

Investigation of Simultaneous and Sequential Cooperative Homotropic Inhibitor Binding to the Catalytic Chamber of SARS-CoV-2 RNA-dependent RNA Polymerase (RdRp).

In our previous report, the unique architecture of the catalytic chamber of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), which harbours two distinctive binding sites, was fully characterized at molecular level. The significant differences in the two binding sites BS1 and BS2 in terms of binding pockets motif, as well as the preferential affinities of eight anti-viral drugs to each of the two binding sites were described. Recent Cryogenic Electron Microscopy (Cryo-EM) studies on the RdRp revealed that two suramin molecules, a SARS-CoV-2 inhibitor, bind to RdRp in two different sites with distinctive interaction landscape.

Therapeutic Path to Triple Knockout: Investigating the Pan-inhibitory Mechanisms of AKT, CDK9, and TNKS2 by a Novel 2-phenylquinazolinone Derivative in Cancer Therapy- An Investigation Therapy.

Background: Blocking the oncogenic Wnt//β-catenin pathway has of late been investigated as a viable therapeutic approach in the treatment of cancer. This involves the multi-targeting of certain members of the tankyrase-kinase family; Tankyrase 2 (TNKS2), Protein Kinase B (AKT), and Cyclin- Dependent Kinase 9 (CDK9), which propagate the oncogenic Wnt/β-catenin signalling pathway.

Methods: During a recent investigation, the pharmacological activity of 2-(4-aminophenyl)-7-chloro- 3H-quinazolin-4-one was repurposed to serve as a 'triple-target' inhibitor of TNKS2, AKT and CDK9.

Enzyme-responsive biomimetic solid lipid nanoparticles for antibiotic delivery against hyaluronidase-secreting bacteria.

In this work, a potent hyaluronidase inhibitor (ascorbyl stearate (AS)) was successfully employed to design vancomycin-loaded solid lipid nanoparticles (VCM-AS-SLNs) with biomimetic and enzyme-responsive features, to enhance the antibacterial efficacy of vancomycin against bacterial-induced sepsis. The VCM-AS-SLNs prepared were biocompatible and had appropriate physicochemical parameters. The VCM-AS-SLNs showed an excellent binding affinity to the bacterial lipase.

The Unusual Architecture of RNA-Dependent RNA Polymerase (RdRp)'s Catalytic Chamber Provides a Potential Strategy for Combination Therapy against COVID-19.

The unusual and interesting architecture of the catalytic chamber of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) was recently explored using Cryogenic Electron Microscopy (Cryo-EM), which revealed the presence of two distinctive binding cavities within the catalytic chamber. In this report, first, we mapped out and fully characterized the variations between the two binding sites, BS1 and BS2, for significant differences in their amino acid architecture, size, volume, and hydrophobicity. This was followed by investigating the preferential binding of eight antiviral agents to each of the two binding sites, BS1 and BS2, to understand the fundamental factors that govern the preferential binding of each drug to each binding site.

Revealing the Role of the Arg and Lys in Shifting Paradigm from BTK Selective Inhibition to the BTK/HCK Dual Inhibition - Delving into the Inhibitory Activity of KIN-8194 against BTK, and HCK in the Treatment of Mutated Waldenström Macroglobulinemia: A Computational Approach.

Background: Despite the early success of Bruton's tyrosine kinase (BTK) inhibitors in the treatment of Waldenström macroglobulinemia (WM), these single-target drug therapies have limitations in their clinical applications, such as drug resistance. Several alternative strategies have been developed, including the use of dual inhibitors, to maximize the therapeutic potential of these drugs.

Objective: Recently, the pharmacological activity of KIN-8194 was repurposed to serve as a 'dual-target' inhibitor of BTK and Hematopoietic Cell Kinase (HCK).

Molecular modelling of SdiA protein by selected flavonoid and terpenes compounds to attenuate virulence in .

is one of the perturbing multidrug resistant (MDR) and ESKAPE pathogens contributing to the mounting morbidity, mortality and extended rate of hospitalization. Its virulence, often regulated by quorum sensing (QS) reinforces the need to explore alternative and prospective antivirulence agents, relatively from plants secondary metabolites. Computer aided drug discovery using molecular modelling techniques offers advantage to investigate prospective drugs to combat MDR pathogens.

Battling BTK mutants with noncovalent inhibitors that overcome Cys481 and Thr474 mutations in Waldenström macroglobulinemia therapy: structural mechanistic insights on the role of fenebrutinib.

Recently, the non-covalent Bruton tyrosine kinase (BTK) inhibitor fenebrutinib was presented as a therapeutic option with strong inhibitory efficacy against a single (C481S) and double (T474S/C481S) BTK variant in the treatment of Waldenström macroglobulinemia (WM). However, the molecular events surrounding its inhibition mechanism towards this variant remain unresolved. Herein, we employed in silico methods such as molecular dynamic simulation coupled with binding free energy estimations to explore the mechanistic activity of the fenebrutinib on (C481S) and (T474S/C481S) BTK variant, at a molecular level.

Probing Alterations in MDM2 Catalytic Core Structure Effect of Garcinia Mangostana Derivatives: Insight from Molecular Dynamics Simulations.

The MDM2-p53 protein-protein interaction is a promising model for researchers to design, study, and discover new anticancer drugs. The design of therapeutically active compounds that can maintain or restore the binding of MDM2 to p53 has been found to limit the oncogenic activities of both. This led to the current development of a group of xanthone-core and cis-imidazoline analogs compounds, among which γ-Mangostin (GM), α-Mangostin (AM), and Nutlin exhibited their MDM2-p53 interaction inhibitory effects.

Co-Binding of JQ1 and Venetoclax Exhibited Synergetic Inhibitory Effect for Cancer Therapy; Potential Line of Treatment for the Waldenström Macroglobulinemia Lymphoma.

In recent times, the development of combination therapy has been a focal point in drug discovery. This article explores the potential synergistic effect of co-administration of Bcl2 inhibitor Venetoclax and BET inhibitor JQ1. We envisioned that the 'dual-site'-binding of Bcl2 has significant prospects and paves the way for the next round of rational design of potent Waldenström macroglobulinemia (WM) therapy.

Talazoparib Dual-targeting on Poly (ADP-ribose) Polymerase-1 and -16 Enzymes Offers a Promising Therapeutic Strategy in Small Cell Lung Cancer Therapy: Insight from Biophysical Computations.

In recent times, inhibition of poly (ADP-ribose) polymerase (PARP) enzymes by pharmacological drugs has attracted much attention as an anticancer therapy. As reported, PARP-16 has been discovered as a novel anticancer target for small cell lung cancer, and that the inhibition of both PARP-16 and PARP-1 by talazoparib can increase the overall effectiveness of talazoparib in the SCLC treatment. In this study, we employed computational approaches to investigate the differential inhibitory potency of Talazoparib on PARP-1 and PARP-16.

Multi-catalytic Sites Inhibition of Bcl2 Induces Expanding of Hydrophobic Groove: A New Avenue Towards Waldenström Macroglobulinemia Therapy.

B-cell lymphoma 2 (Bcl2) is a key protein regulator of apoptosis. The hydrophobic groove in Bcl2 is a unique structural feature to this class of enzymes and found to have a profound impact on protein overall structure, function, and dynamics. Dynamics of the hydrophobic groove is an essential determinant of the catalytic activity of Bcl2, an implicated protein in Waldenström macroglobulinemia (WM).

The antioxidant and antidiabetic potentials of polyphenolic-rich extracts of (Linn.).

In this study, the rhizome of L was investigated for its antioxidant and antidiabetic effects using and experimental models. Its crude extracts (ethyl acetate, ethanol and aqueous) were screened for their antioxidant activity using ferric-reducing antioxidant power (FRAP) and 1,1-diphenyl-2-picrylhydrazyl (DPPH), as well as their inhibitory effect on α-glucosidase enzyme. Subsequently, the extracts were subjected to Gas Chromatography-Mass Spectrometry (GC-MS) analysis to elucidate their possible bioactive compounds.

Distinguishing the optimal binding mechanism through reversible and irreversible inhibition analysis of HSP72 protein in cancer therapy.

Over the past two decades, covalent inhibitors have gained much interest and are living up to their reputation as a powerful tool in drug discovery. Covalent inhibitors possess several significant advantages, including increased biochemical efficiency, prolonged duration and the ability to target shallow, solvent-exposed substrate-binding domains. One of the enzymes that have been both covalently and non-covalently targeted is the heat shock protein 72 (HSP72).

Coupling of HSP72 α-Helix Subdomains by the Unexpected Irreversible Targeting of Lysine-56 over Cysteine-17; Coevolution of Covalent Bonding.

Covalent inhibition has recently gained a resurgence of interest in several drug discovery areas. The expansion of this approach is based on evidence elucidating the selectivity and potency of covalent inhibitors when bound to particular amino acids of a biological target. The unexpected covalent inhibition of heat shock protein 72 (HSP72) by covalently targeting Lys-56 instead of Cys-17 was an interesting observation.

Covalent Versus Non-covalent Enzyme Inhibition: Which Route Should We Take? A Justification of the Good and Bad from Molecular Modelling Perspective.

The pace and efficiency of drug target strategies have been emanating debates among researchers in the field of drug development. Covalent inhibitors possess significant advantages over non-covalent inhibitors, such that covalent warheads can target rare residues of a particular target protein, thus leading to the development of highly selective inhibitors. However, toxicity can be a real challenge related to this class of therapeutics.

'Piperazining' the catalytic gatekeepers: unraveling the pan-inhibition of SRC kinases; LYN, FYN and BLK by masitinib.

Blocking oncogenic signaling of B-cell receptor (BCR) has been explored as a viable strategy in the treatment of diffuse large B-cell lymphoma. Masitinib is shown to multitarget LYN, FYN and BLK kinases that propagate BCR signals to downstream effectors. However, the molecular mechanisms of its selectivity and pan-inhibition remain elusive.

Turning to Computer-aided Drug Design in the Treatment of Diffuse Large B-cell Lymphoma: Has it been Helpful?

Introduction: Amidst the numerous effective therapeutic options available for the treatment of Diffuse Large B-cell Lymphoma (DLBCL), about 30-40% of patients treated with first-line chemoimmunotherapy still experience a relapse or refractory DLBCL. This has necessitated a continuous search for new therapeutic agents to augment the existing therapeutic arsenal.

Methods: The dawn of Computer-Aided Drug Design (CADD) in the drug discovery process has accounted for persistency in the application of computational approaches either alone or in combinatorial strategies with experimental methods towards the identification of potential hit compounds with high therapeutic efficacy in abrogating DLBCL.