Atomistic simulations reveal impacts of missense mutations on the structure and function of SynGAP1.

De novo mutations in the synaptic GTPase activating protein (SynGAP) are associated with neurological disorders like intellectual disability, epilepsy, and autism. SynGAP is also implicated in Alzheimer's disease and cancer. Although pathogenic variants are highly penetrant in neurodevelopmental conditions, a substantial number of them are caused by missense mutations that are difficult to diagnose.

Building shape-focused pharmacophore models for effective docking screening.

The performance of molecular docking can be improved by comparing the shape similarity of the flexibly sampled poses against the target proteins' inverted binding cavities. The effectiveness of these pseudo-ligands or negative image-based models in docking rescoring is boosted further by performing enrichment-driven optimization. Here, we introduce a novel shape-focused pharmacophore modeling algorithm O-LAP that generates a new class of cavity-filling models by clumping together overlapping atomic content via pairwise distance graph clustering.

Virtual Screening Strategy to Identify Retinoic Acid-Related Orphan Receptor γt Modulators.

Molecular docking is a key method used in virtual screening (VS) campaigns to identify small-molecule ligands for drug discovery targets. While docking provides a tangible way to understand and predict the protein-ligand complex formation, the docking algorithms are often unable to separate active ligands from inactive molecules in practical VS usage. Here, a novel docking and shape-focused pharmacophore VS protocol is demonstrated for facilitating effective hit discovery using retinoic acid receptor-related orphan receptor gamma t (RORγt) as a case study.

Ligand-Enhanced Negative Images Optimized for Docking Rescoring.

Despite the pivotal role of molecular docking in modern drug discovery, the default docking scoring functions often fail to recognize active ligands in virtual screening campaigns. Negative image-based rescoring improves docking enrichment by comparing the shape/electrostatic potential (ESP) of the flexible docking poses against the target protein's inverted cavity volume. By optimizing these negative image-based (NIB) models using a greedy search, the docking rescoring yield can be improved massively and consistently.

Rational design, optimization, and biological evaluation of novel α-Phosphonopropionic acids as covalent inhibitors of Rab geranylgeranyl transferase.

Rab geranylgeranyltransferase (GGTase-II, RGGT) catalyses the post-translational modification of eukaryotic Rab GTPases, proteins implicated in several pathologies, including cancer, diabetes, neurodegenerative, and infectious diseases. Thus, RGGT inhibitors are believed to be a potential platform for the development of drugs and tools for studying processes related to the abnormal activity of Rab GTPases. Here, a series of new α-phosphonocarboxylates have been prepared in the first attempt of rational design of covalent inhibitors of RGGT derived from non-covalent inhibitors.

Computational Study on the Inhibitory Effect of Natural Compounds against the SARS-CoV-2 Proteins.

COVID-19 is more virulent and challenging to human life. In India, the Ministry of AYUSH recommended some strategies through Siddha, homeopathy, and other methods to effectively manage COVID-19 (Guidelines for AYUSH Clinical Studies in COVID-19, 2020). and homeopathy medicines are in use for the prevention and treatment of COVID-19 infection; however, the mechanism of action is less explored.

Optimization of Cavity-Based Negative Images to Boost Docking Enrichment in Virtual Screening.

Molecular docking is a key in silico method used routinely in modern drug discovery projects. Although docking provides high-quality ligand binding predictions, it regularly fails to separate the active compounds from the inactive ones. In negative image-based rescoring (R-NiB), the shape/electrostatic potential (ESP) of docking poses is compared to the negative image of the protein's ligand binding cavity.

Sdfconf: A Novel, Flexible, and Robust Molecular Data Management Tool.

Projects in chemo- and bioinformatics often consist of scattered data in various types and are difficult to access in a meaningful way for efficient data analysis. Data is usually too diverse to be even manipulated effectively. Sdfconf is data manipulation and analysis software to address this problem in a logical and robust manner.

A holistic view on c-Kit in cancer: Structure, signaling, pathophysiology and its inhibitors.

Receptor tyrosine kinases play an important role in many cellular processes, and their dysregulation leads to diseases, most importantly cancer. One such receptor tyrosine kinase is c-Kit, a type-III receptor tyrosine kinase, which is involved in various intracellular signaling pathways. The role of different mutant isoforms of c-Kit has been established in several types of cancers.

Coumarins as Tool Compounds to Aid the Discovery of Selective Function Modulators of Steroid Hormone Binding Proteins.

Steroid hormones play an essential role in a wide variety of actions in the body, such as in metabolism, inflammation, initiating and maintaining sexual differentiation and reproduction, immune functions, and stress response. Androgen, aromatase, and sulfatase pathway enzymes and nuclear receptors are responsible for steroid biosynthesis and sensing steroid hormones. Changes in steroid homeostasis are associated with many endocrine diseases.

Substrate Selectivity of Coumarin Derivatives by Human CYP1 Enzymes: In Vitro Enzyme Kinetics and In Silico Modeling.

Of the three enzymes in the human cytochrome P450 family 1, CYP1A2 is an important enzyme mediating metabolism of xenobiotics including drugs in the liver, while CYP1A1 and CYP1B1 are expressed in extrahepatic tissues. Currently used CYP substrates, such as 7-ethoxycoumarin and 7-ethoxyresorufin, are oxidized by all individual CYP1 forms. The main aim of this study was to find profluorescent coumarin substrates that are more selective for the individual CYP1 forms.

Detection of Binding Sites on SARS-CoV-2 Spike Protein Receptor-Binding Domain by Molecular Dynamics Simulations in Mixed Solvents.

The novel SARS-CoV-2 uses ACE2 (Angiotensin-Converting Enzyme 2) receptor as an entry point. Insights on S protein receptor-binding domain (RBD) interaction with ACE2 receptor and drug repurposing has accelerated drug discovery for the novel SARS-CoV-2 infection. Finding small molecule binding sites in S protein and ACE2 interface is crucial in search of effective drugs to prevent viral entry.

Negative Image-Based Rescoring: Using Cavity Information to Improve Docking Screening.

Molecular docking produces often lackluster results in real-life virtual screening assays that aim to discover novel drug candidates or hit compounds. The problem lies in the inability of the default docking scoring to properly estimate the Gibbs free energy of binding, which impairs the recognition of the best binding poses and the separation of active ligands from inactive compounds. Negative image-based rescoring (R-NiB) provides both effective and efficient way for re-ranking the outputted flexible docking poses to improve the virtual screening yield.

Negative Image-Based Screening: Rigid Docking Using Cavity Information.

Rational drug discovery relies heavily on molecular docking-based virtual screening, which samples flexibly the ligand binding poses against the target protein's structure. The upside of flexible docking is that the geometries of the generated docking poses are adjusted to match the residue alignment inside the target protein's ligand-binding pocket. The downside is that the flexible docking requires plenty of computing resources and, regardless, acquiring a decent level of enrichment typically demands further rescoring or post-processing.

Molecular docking and oxidation kinetics of 3-phenyl coumarin derivatives by human CYP2A13.

CYP2A13 enzyme is expressed in human extrahepatic tissues, while CYP2A6 is a hepatic enzyme. Reactions catalysed by CYP2A13 activate tobacco-specific nitrosamines and some other toxic xenobiotics in lungs.To compare oxidation characteristics and substrate-enzyme active site interactions in CYP2A13 vs CYP2A6, we evaluated CYP2A13 mediated oxidation characteristics of 23 coumarin derivatives and modelled their interactions at the enzyme active site.

Screening of Natural Products Targeting SARS-CoV-2-ACE2 Receptor Interface - A MixMD Based HTVS Pipeline.

The COVID-19 pandemic, caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a severe global health crisis now. SARS-CoV-2 utilizes its Spike protein receptor-binding domain (S-protein) to invade human cell through binding to Angiotensin-Converting Enzyme 2 receptor (ACE2). S-protein is the key target for many therapeutics and vaccines.

Inhibition of human CYP1 enzymes by a classical inhibitor α-naphthoflavone and a novel inhibitor N-(3, 5-dichlorophenyl)cyclopropanecarboxamide: An in vitro and in silico study.

Enzymes in the cytochrome P450 family 1 (CYP1) catalyze metabolic activation of procarcinogens and deactivation of certain anticancer drugs. Inhibition of these enzymes is a potential approach for cancer chemoprevention and treatment of CYP1-mediated drug resistance. We characterized inhibition of human CYP1A1, CYP1A2, and CYP1B1 enzymes by the novel inhibitor N-(3,5-dichlorophenyl)cyclopropanecarboxamide (DCPCC) and α-naphthoflavone (ANF).

In vitro glucuronidation of 7-hydroxycoumarin derivatives in intestine and liver microsomes of Beagle dogs.

Beagle dog is a standard animal model for evaluating nonclinical pharmacokinetics of new drug candidates. Glucuronidation in intestine and liver is an important first-pass drug metabolic pathway, especially for phenolic compounds. This study evaluated the glucuronidation characteristics of several 7-hydroxycoumarin derivatives in beagle dog's intestine and liver in vitro.

Getting Docking into Shape Using Negative Image-Based Rescoring.

The failure of default scoring functions to ensure virtual screening enrichment is a persistent problem for the molecular docking algorithms used in structure-based drug discovery. To remedy this problem, elaborate rescoring and postprocessing schemes have been developed with a varying degree of success, specificity, and cost. The negative image-based rescoring (R-NiB) has been shown to improve the flexible docking performance markedly with a variety of drug targets.

Fragment- and negative image-based screening of phosphodiesterase 10A inhibitors.

A novel virtual screening methodology called fragment- and negative image-based (F-NiB) screening is introduced and tested experimentally using phosphodiesterase 10A (PDE10A) as a case study. Potent PDE10A-specific small-molecule inhibitors are actively sought after for their antipsychotic and neuroprotective effects. The F-NiB combines features from both fragment-based drug discovery and negative image-based (NIB) screening methodologies to facilitate rational drug discovery.

A Practical Perspective: The Effect of Ligand Conformers on the Negative Image-Based Screening.

Negative image-based (NIB) screening is a rigid molecular docking methodology that can also be employed in docking rescoring. During the NIB screening, a negative image is generated based on the target protein's ligand-binding cavity by inverting its shape and electrostatics. The resulting NIB model is a drug-like entity or pseudo-ligand that is compared directly against ligand 3D conformers, as is done with a template compound in the ligand-based screening.

Suitability of MMGBSA for the selection of correct ligand binding modes from docking results.

The estimation of the correct binding mode and affinity of a ligand into a target protein using computational methods is challenging. However, docking can introduce poses from which the correct binding mode could be identified using other methods. Here, we analyzed the reliability of binding energy estimation using the molecular mechanics-generalized Born surface area (MMGBSA) method without and with energy minimization to identify the likely ligand binding modes within docking results.

Development of new Coumarin-based profluorescent substrates for human cytochrome P450 enzymes.

Cytochrome P450 (CYP) enzymes constitute an essential xenobiotic metabolizing system that regulates the elimination of lipophilic compounds from the body. Convenient and affordable assays for CYP enzymes are important for assessing these metabolic pathways. In this study, 10 novel profluorescent coumarin derivatives with various substitutions at carbons 3, 6 and 7 were developed.

Discovery of Retinoic Acid-Related Orphan Receptor γt Inverse Agonists via Docking and Negative Image-Based Screening.

Retinoic acid-related orphan receptor γt (RORγt) has a vital role in the differentiation of T-helper 17 (TH17) cells. Potent and specific RORγt inverse agonists are sought for treating TH17-related diseases such as psoriasis, rheumatoid arthritis, and type 1 diabetes. Here, the aim was to discover novel RORγt ligands using both standard molecular docking and negative image-based screening.

Effects of cold acclimation and dsRNA injections on Gs1l gene splicing in Drosophila montana.

Alternative splicing, in which one gene produce multiple transcripts, may influence how adaptive genes respond to specific environments. A newly produced transcriptome of Drosophila montana shows the Gs1-like (Gs1l) gene to express multiple splice variants and to be down regulated in cold acclimated flies with increased cold tolerance. Gs1l's effect on cold tolerance was further tested by injecting cold acclimated and non-acclimated flies from two distantly located northern and southern fly populations with double stranded RNA (dsRNA) targeting Gs1l.