Integration of 3D-QSAR, molecular docking, and machine learning techniques for rational design of nicotinamide-based SIRT2 inhibitors.

Selective inhibitors of sirtuin-2 (SIRT2) are increasingly recognized as potential therapeutics for cancer and neurodegenerative diseases. Derivatives of 5-((3-amidobenzyl)oxy)nicotinamides have been identified as some of the most potent and selective SIRT2 inhibitors reported to date (​Ai et al., 2016​; ​Ai et al.

Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer.

Histone deacetylases (HDACs) are the major regulators of the balance of acetylation of histone and non-histone proteins. In contrast to other HDAC isoforms, HDAC6 is mainly involved in maintaining the acetylation balance of many non-histone proteins. Therefore, the overexpression of HDAC6 is associated with tumorigenesis, invasion, migration, survival, apoptosis and growth of various malignancies.

Reversible Control of RNA Splicing by Photoswitchable Small Molecules.

Dynamics are intrinsic to both RNA function and structure. Yet, the available means to precisely provide RNA-based processes with spatiotemporal resolution are scarce. Here, our work pioneers a reversible approach to regulate RNA splicing within primary patient-derived cells by synthetic photoswitches.

Correlating Basal Gene Expression across Chemical Sensitivity Data to Screen for Novel Synergistic Interactors of HDAC Inhibitors in Pancreatic Carcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies. Development of the chemoresistance in the PDAC is one of the key contributors to the poor survival outcomes and the major reason for urgent development of novel pharmacological approaches in a treatment of PDAC. Systematically tailored combination therapy holds the promise for advancing the treatment of PDAC.

SIRT2i_Predictor: A Machine Learning-Based Tool to Facilitate the Discovery of Novel SIRT2 Inhibitors.

A growing body of preclinical evidence recognized selective sirtuin 2 (SIRT2) inhibitors as novel therapeutics for treatment of age-related diseases. However, none of the SIRT2 inhibitors have reached clinical trials yet. Transformative potential of machine learning (ML) in early stages of drug discovery has been witnessed by widespread adoption of these techniques in recent years.

Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation.

Isoform-selective histone deacetylase (HDAC) inhibition is promoted as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors. Despite this presumed benefit, considerably more non-selective HDAC inhibitors have undergone clinical trials. In this report, we detail the design and discovery of potent HDAC inhibitors, with 1-benzhydryl piperazine as a surface recognition group, that differ in hydrocarbon linker.

Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics.

Considerations of binding pocket dynamics are one of the crucial aspects of the rational design of binders. Identification of alternative conformational states or cryptic subpockets could lead to the discovery of completely novel groups of the ligands. However, experimental characterization of pocket dynamics, besides being expensive, may not be able to elucidate all of the conformational states relevant for drug discovery projects.

Quinazoline-based analog of adenine as an antidote against MLL-rearranged leukemia cells: synthesis, inhibition assays and docking studies.

Post-translational modifications of histones constitute a dynamic process impacting gene expression. A well-studied modification is lysine methylation. Among the lysine histone methyltransferases, DOT1L is implicated in various diseases, making it a very interesting target for drug discovery.

Bistable Photoswitch Allows in Vivo Control of Hematopoiesis.

Optical control has enabled functional modulation in cell culture with unparalleled spatiotemporal resolution. However, current tools for in vivo manipulation are scarce. Here, we design and implement a genuine optochemical probe capable of achieving hematopoietic control in zebrafish.

Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention.

The dysregulation of gene expression is a critical event involved in all steps of tumorigenesis. Aberrant histone and non-histone acetylation modifications of gene expression due to the abnormal activation of histone deacetylases (HDAC) have been reported in hematologic and solid types of cancer. In this sense, the cancer-associated epigenetic alterations are promising targets for anticancer therapy and chemoprevention.

Synthesis and Biological Activity of a Cytostatic Inhibitor of MLLr Leukemia Targeting the DOT1L Protein.

Histone methyltransferase DOT1L catalyzes mono-, di- and trimethylation of histone 3 at lysine residue 79 (H3K79) and hypermethylation of H3K79 has been linked to the development of acute leukemias characterized by the MLL (mixed-lineage leukemia) rearrangements (MLLr cells). The inhibition of H3K79 methylation inhibits MLLr cells proliferation, and an inhibitor specific for DOT1L, pinometostat, was in clinical trials (Phase Ib/II). However, the compound showed poor pharmacological properties.

An Integrative in silico Drug Repurposing Approach for Identification of Potential Inhibitors of SARS-CoV-2 Main Protease.

Considering the urgent need for novel therapeutics in ongoing COVID-19 pandemic, drug repurposing approach might offer rapid solutions comparing to de novo drug design. In this study, we designed an integrative in silico drug repurposing approach for rapid selection of potential candidates against SARS-CoV-2 Main Protease (M ). To screen FDA-approved drugs, we implemented structure-based molecular modelling techniques, physiologically-based pharmacokinetic (PBPK) modelling of drugs disposition and data mining analysis of drug-gene-COVID-19 association.

Fragment-Based Drug Design of Selective HDAC6 Inhibitors.

Medicinal chemistry society has enough arguments to justify the usage of fragment-based drug design (FBDD) methodologies for the identification of lead compounds. Since the FDA approval of three kinase inhibitors - vemurafenib, venetoclax, and erdafitinib, FBDD has become a challenging alternative to high-throughput screening methods in drug discovery. The following protocol presents in silico drug design of selective histone deacetylase 6 (HDAC6) inhibitors through a fragment-based approach.

Synthesis, in silico, and in vitro studies of novel dopamine D and D receptor ligands.

Dopamine is an important neurotransmitter in the human brain and its altered concentrations can lead to various neurological diseases. We studied the binding of novel compounds at the dopamine D (D R) and D (D R) receptor subtypes, which belong to the D -like receptor family. The synthesis, in silico, and in vitro characterization of 10 dopamine receptor ligands were performed.

Methods for Design of Kinase Inhibitors as Anticancer Drugs.

Rational drug design implies usage of molecular modeling techniques such as pharmacophore modeling, molecular dynamics, virtual screening, and molecular docking to explain the activity of biomolecules, define molecular determinants for interaction with the drug target, and design more efficient drug candidates. Kinases play an essential role in cell function and therefore are extensively studied targets in drug design and discovery. Kinase inhibitors are clinically very important and widely used antineoplastic drugs.

Structure-based design of selective histone deacetylase 6 zinc binding groups.

The binding site of the second catalytic domain of human histone deacetylase 6 (HDAC6 CDII) has structural features that differ from the other human orthologues, being also mainly responsible for the overall enzymatic activity of this isoform. Aiming to identify new fragments as a possible novel selective zinc binding group (ZBG) for HDAC6 CDII, two fragment libraries were designed: one library consisting of known chelators and a second one using the fragments of the ZINC15 database. The most promising fragments identified in a structure-based virtual screening of designed libraries were further evaluated through molecular docking and molecular dynamics simulations.

Modulating Protein-Protein Interactions with Visible-Light-Responsive Peptide Backbone Photoswitches.

Life relies on a myriad of carefully orchestrated processes, in which proteins and their direct interplay ultimately determine cellular function and disease. Modulation of this complex crosstalk has recently attracted attention, even as a novel therapeutic strategy. Herein, we describe the synthesis and characterization of two visible-light-responsive peptide backbone photoswitches based on azobenzene derivatives, to exert optical control over protein-protein interactions (PPI).