Optimizing antibody stability and efficacy in CD47- SIRPα inhibition via computational approaches.

CD47, a cell surface protein, serves as a "don't eat me" signal that prevents immune cells from engulfing healthy cells upon its interaction with SIRPα. Cancer cells exploit this mechanism by overexpressing CD47 to evade immune destruction. Blocking the interaction between CD47 and its receptor, SIRPα, is a promising therapeutic strategy.

Cancer pharmacoinformatics: Databases and analytical tools.

Cancer is a subject of extensive investigation, and the utilization of omics technology has resulted in the generation of substantial volumes of big data in cancer research. Numerous databases are being developed to manage and organize this data effectively. These databases encompass various domains such as genomics, transcriptomics, proteomics, metabolomics, immunology, and drug discovery.

Indole-3 Carbinol and Diindolylmethane Mitigated β-Amyloid-Induced Neurotoxicity and Acetylcholinesterase Enzyme Activity: In Silico, In Vitro, and Network Pharmacology Study.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by beta-amyloid (Aβ) deposition and increased acetylcholinesterase (AchE) enzyme activities. Indole 3 carbinol (I3C) and diindolylmethane (DIM) are reported to have neuroprotective activities against various neurological diseases, including ischemic stroke, Parkinson's disease, neonatal asphyxia, depression, stress, neuroinflammation, and excitotoxicity, except for AD. In the present study, we have investigated the anti-AD effects of I3C and DIM.

Interplay of PROTAC Complex Dynamics for Undruggable Targets: Insights into Ternary Complex Behavior and Linker Design.

Protein degraders, such as bifunctional proteolysis-targeting chimeras (PROTACs), selectively eliminate target proteins by leveraging the natural protein degradation machinery. PROTACs bridge the target protein with an E3 ligase, which induces ubiquitination and degradation. Investigating ternary complex structures elucidates the molecular mechanisms of their formation and degradation.

Exploring the binding dynamics of covalent inhibitors within active site of PL in SARS-CoV-2.

In the global fight against the COVID-19 pandemic caused by the highly transmissible SARS-CoV-2 virus, the search for potent medications is paramount. With a focused investigation on the SARS-CoV-2 papain-like protease (PL) as a promising therapeutic target due to its pivotal role in viral replication and immune modulation, the catalytic triad of PL comprising Cys111, His272, and Asp286, highlights Cys111 as an intriguing nucleophilic center for potential covalent bonds with ligands. The detailed analysis of the binding site unveils crucial interactions with both hydrophobic and polar residues, demonstrating the structural insights of the cavity and deepening our understanding of its molecular landscape.

Protein tyrosine phosphatase inhibitors: a patent review and update (2012-2023).

Introduction: Protein tyrosine phosphatases (PTPs), essential and evolutionarily highly conserved enzymes, govern cellular functions by modulating tyrosine phosphorylation, a pivotal post-translational modification for signal transduction. The recent strides in phosphatase drug discovery, leading to the identification of selective modulators for enzymes, restoring interest in the therapeutic targeting of protein phosphatases.

Areas Covered: The compilation of patents up to the year 2023 focuses on the efficacy of various classes of Tyrosine phosphatases and their inhibitors, detailing their chemical structure and biochemical characteristics.

Targeting an Old Foe for Cancer: A Molecular Dynamics Perspective to Unravel the Specific Binding Nature of 2-Methoxy Estradiol to Human β-Tubulin Isotypes.

Microtubules, composed of α- and β-tubulin subunits are crucial for cell division with their dynamic tissue-specificity which is dictated by expression of isotypes. These isotypes differ in carboxy-terminal tails (CTTs), rich in negatively charged acidic residues in addition to the differences in the composition of active site residues. 2-Methoxy estradiol (2-ME) is the first antimicrotubule agent that showed less affinity toward hemopoietic-specific β1 isotype consequently preventing myelosuppression toxicity.

An study of protein-protein interactions and design of novel peptides for TrkA in ameloblastoma.

Ameloblastoma is a benign odontogenic jawbone tumor. The binding of Nerve growth factor (NGF) to receptor tyrosine kinase A (TrkA) promotes cell survival, proliferation, and differentiation PI3K/AKT and Ras/MAPK signaling. Although the exact cause of ameloblastoma remains unknown, elevated levels of NGF and TrkA expression in ameloblastoma are associated with aggressive tumor behavior and poor patient outcomes.

Exploring the efficacy of ethnomedicinal plants of Himalayan region against the malaria parasite.

Ethnopharmacological Relevance: Plasmodium falciparum multi-drug resistant (MDR) strains are a great challenge to global health care. This predicament implies the urgent need to discover novel antimalarial drugs candidate from alternative natural sources. The Himalaya constitute a rich repository of medicinal plants which have been used traditionally in the folklore medicine since ages and having no scientific evidence for their activity.

Breaking the 'don't eat me' signal: in silico design of CD47-directed peptides for cancer immunotherapy.

The leading cause of death worldwide is cancer. Although there are various therapies available to treat cancer, finding a successful one can be like searching for a needle in a haystack. Immunotherapy appears to be one of those needles in the haystack of cancer treatment.

Emerging Therapies and Therapeutic Targets for Composite Liver Disease: NASH.

Background: Liver diseases continue to destroy the lives of people, one of which is known as Non-alcoholic Steatohepatitis (NASH) that becomes a serious liver disease all around the world over the last few years. Non-alcoholic Steatohepatitis (NASH) is a progressive form of Nonalcoholic Fatty Liver Disease (NAFLD) and is characterized by liver steatosis, inflammation, different degrees of fibrosis, and hepatocellular injury. The inflammatory mediators play a vital role in the transition of Non-alcoholic Fatty Liver (NAFL) to Non-alcoholic Steatohepatitis (NASH), which further leads to Hepatocellular Carcinoma (HCC) and becomes a cause of liver transplantation.

Water network chemistry to exploit the nature of catalytic water molecules in DNA gyrase: a computational study to understand the binding mechanism of fluoroquinolones.

The dynamics of DNA gyrase and mutants of DNA gyrA such as G88A, A90V, S91P, D94A, D94G, D94N, D94Y; and double-point mutant (S91P-D94G), are meticulously investigated using computational approaches. Molecular dynamics (MD) and hydration thermodynamics have shed light on the fundamental, mechanistic basis of mutations on the conformational stability of Quinolone Binding Pocket (QBP) of DNA gyrase. Analysis of MD results revealed the displacement of a single crystal water molecule (HOH201) from the catalytic site of wild-type (WT) and mutants of DNA gyrA.

Bifunctional robots inducing targeted protein degradation.

The gaining importance of Targeted Protein Degradation (TPD) and PROTACs (PROteolysis-TArgeting Chimeras) have drawn the scientific community's attention. PROTACs are considered bifunctional robots owing to their avidity for the protein of interest (POI) and E3-ligase, which induce the ubiquitination of POI. These molecules are based on event-driven pharmacology and are applicable in different conditions such as oncology, antiviral, neurodegenerative disease, acne etc.

Discovery and evaluation of biphenyl derivatives of 2-iminobenzimidazoles as prototype dual PTP1B inhibitors and AMPK activators with in vivo antidiabetic activity.

This work describes the synthesis of series hydrobromides of N-(4-biphenyl)methyl-N'-dialkylaminoethyl-2-iminobenzimidazoles, which, due to the presence of two privileged structural fragments (benzimidazole and biphenyl moieties), can be considered as bi-privileged structures. Compound 7a proved to activate AMP-activated kinase (AMPK) and simultaneously inhibit protein tyrosine phosphatase 1B (PTP1B) with similar potency. This renders it an interesting prototype of potential antidiabetic agents with a dual-target mechanism of action.

Identification of prospective covalent inhibitors for SARS-CoV-2 main protease using structure-based approach.

The rapid global spread of SARS-CoV-2 has recently caused havoc and forced the world into a state of the pandemic causing respiratory, gastrointestinal, hepatic, and neurologic diseases. It persistently, through mutation, develops into new variants of the virus that have appeared over time. As main protease (M) is involved in proteolysis of two overlapping polyproteins and to produce 16 non-structural proteins having a paramount factor in the virus replication that have a cysteine-histidine catalytic dyad.

Identification of Potential ACE2-Derived Peptide Mimetics in SARS-CoV-2 Omicron Variant Therapeutics using Computational Approaches.

The COVID-19 pandemic has become a global health challenge because of the emergence of distinct variants. Omicron, a new variant, is recognized as a variant of concern (VOC) by the World Health Organization (WHO) because of its higher mutations and accelerated human infection. The infection rate is strongly dependent on the binding rate of the receptor binding domain (RBD) against human angiotensin converting enzyme-2 (ACE2) receptor.

The Role of Water Network Chemistry in Proteins: A Structural Bioinformatics Perspective in Drug Discovery and Development.

Background: Although water is regarded as a simple molecule, its ability to create hydrogen bonds makes it a highly complex molecule that is crucial to molecular biology. Water molecules are extremely small and are made up of two different types of atoms, each of which plays a particular role in biological processes. Despite substantial research, understanding the hydration chemistry of protein-ligand complexes remains difficult.

Molecular dynamic assisted investigation on impact of mutations in deazaflavin dependent nitroreductase against pretomanid: a computational study.

In the past decade, TB drugs belonging to the nitroimidazole class, pretomanid and delamanid, have been authorised to treat MDR-TB and XDR-TB. With a novel inhibition mechanism and a reduction in the span of treatment, it is now being administered in various combinations. This approach is not the ultimate remedy since the target protein Deazaflavin dependent nitroreductase (Ddn) has a high mutation frequency, and already pretomanid resistant clinical isolates are reported in various studies.

Protein degradation: a novel computational approach to design protein degrader probes for main protease of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has afflicted many lives and led to approvals of drugs and vaccines for emergency use. Even though vaccines have emerged, the high mortality of COVID-19 and its insurgent proliferation throughout the masses commands an innovative therapeutic proposition for the treatment. Targeted protein degradation has been applied to various disease domains and we propose that it could be incredibly beneficial to tackle the current pandemic.

Rapid structure-based identification of potential SARS-CoV-2 main protease inhibitors.

The COVID-19 outbreak has thrown the world into an unprecedented crisis. It has posed a challenge to scientists around the globe who are working tirelessly to combat this pandemic. We herein report a set of molecules that may serve as possible inhibitors of the SARS-CoV-2 main protease.

Identification of potential SARS-CoV-2 M inhibitors integrating molecular docking and water thermodynamics.

The COVID-19 pandemic is an ongoing global health emergency caused by a newly discovered coronavirus SARS-CoV-2. The entire scientific community across the globe is working diligently to tackle this unprecedented challenge. studies have played a crucial role in the current situation by expediting the process of identification of novel potential chemotypes targeting the viral receptors.

Computational and Biological Investigations on Abl1 Tyrosine Kinase: A Review.

Abl1 tyrosine kinase is a validated target for the treatment of chronic myeloid leukemia. It is a form of cancer that is difficult to treat and much research is being done to identify new molecular entities and to tackle drug resistance issues. In recent years, drug resistance of Abl1 tyrosine kinase has become a major healthcare concern.

A Multi-Perspective Review on Dengue Research.

Dengue fever is a disease which is caused by a family of viruses named Flaviviridae which are transmitted by female Aedes mosquitoes. Today, this is endemic in more than 100 nations in the World Health Organization's African, Americas, Eastern Mediterranean, South-East Asia and Western Pacific locales. The treatment of typical dengue is focused on relieving the symptoms and signs.

Screening and identification of potential PTP1B allosteric inhibitors using in silico and in vitro approaches.

Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for Type 2 diabetes due to its specific role as a negative regulator of insulin signaling pathways. Discovery of active site directed PTP1B inhibitors is very challenging due to highly conserved nature of the active site and multiple charge requirements of the ligands, which makes them non-selective and non-permeable. Identification of the PTP1B allosteric site has opened up new avenues for discovering potent and selective ligands for therapeutic intervention.

Cell wall permeability assisted virtual screening to identify potential direct InhA inhibitors of Mycobacterium tuberculosis and their biological evaluation.

The arising cases of isoniazid-resistance have motivated research interests toward new class of molecules known as direct InhA inhibitors. Here, a combine approach of shape-based pharmacophore and descriptor-based 2D QSAR was used to identify the potential direct InhA inhibitors. The approach is duly assisted with in vitro testing and molecular dynamics simulations.