PCW-A1001, AI-assisted design approach to design a selective inhibitor for FLT-3(D835Y) in acute myeloid leukemia.

Treating acute myeloid leukemia (AML) by targeting FMS-like tyrosine kinase 3 (FLT-3) is considered an effective treatment strategy. By using AI-assisted hit optimization, we discovered a novel and highly selective compound with desired drug-like properties with which to target the FLT-3 (D835Y) mutant. In the current study, we applied an AI-assisted design approach to identify a novel inhibitor of FLT-3 (D835Y).

Quantum-based machine learning and AI models to generate force field parameters for drug-like small molecules.

Force fields for drug-like small molecules play an essential role in molecular dynamics simulations and binding free energy calculations. In particular, the accurate generation of partial charges on small molecules is critical to understanding the interactions between proteins and drug-like molecules. However, it is a time-consuming process.

QM/MM Simulations for the Broken-Symmetry Catalytic Reaction Mechanism of Human Arginase I.

Human arginase I (HARGI) is a metalloprotein highly expressed in the liver cytosol and catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. Understanding the reaction mechanism would be highly helpful to design new inhibitor molecules for HARGI as it is a target for heart- and blood-related diseases. In this study, we explored the hydrolysis reaction mechanism of HARGI with antiferromagnetic and ferromagnetic coupling between two Mn(II) ions at the catalytic site by employing molecular dynamics simulations coupled with quantum mechanics and molecular mechanics (QM/MM).

Destabilization of amyloid fibrils on interaction with MoS-based nanomaterials.

The present work is motivated by the established concept that the structure and energetics of biomacromolecules can be modulated by confining their dimensions in the nanoscale. In particular, here we use force-field methods to understand the stability of amyloid fibrils at nanostructured interfaces, which can be useful for the development of new therapeutics for Alzheimer's disease. We explore the binding modes and structural properties of fibrils at the interface of molybdenum disulphide nanotubes and the nanosurface using classical molecular dynamics simulations.

Effect of Familial Mutations on the Interconversion of α-Helix to β-Sheet Structures in an Amyloid-Forming Peptide: Insight from Umbrella Sampling Simulations.

Understanding the initial events of aggregation of amyloid β monomers to form β-sheet rich fibrils is useful for the development of therapeutics for Alzheimer's disease. In this context, the changes in energetics involved in the aggregation of helical amyloid β monomers into β-sheet rich dimers have been investigated using umbrella sampling simulations and density functional theory calculations. The results from umbrella sampling simulations for the free energy profile for the interconversion closely agree with the results of density functional theory calculations.

Free Energy Landscape for Alpha-Helix to Beta-Sheet Interconversion in Small Amyloid Forming Peptide under Nanoconfinement.

Understanding the mechanism of fibrillization of amyloid forming peptides could be useful for the development of therapeutics for Alzheimer's disease (AD). Taking this standpoint, we have explored in this work the free energy profile for the interconversion of monomeric and dimeric forms of amyloid forming peptides into different secondary structures namely beta-sheet, helix, and random coil in aqueous solution using umbrella sampling simulations and density functional theory calculations. We show that the helical structures of amyloid peptides can form β sheet rich aggregates through random coil conformations in aqueous condition.

Bent Keto Form of Curcumin, Preferential Stabilization of Enol by Piperine, and Isomers of Curcumin∩Cyclodextrin Complexes: Insights from Ion Mobility Mass Spectrometry.

A detailed examination of collision cross sections (CCSs) coupled with computational methods has revealed new insights into some of the key questions centered around curcumin, one of the most intensively studied natural therapeutic agents. In this study, we have distinguished the structures and conformers of the well-known enol and the far more elusive keto form of curcumin by using ion mobility mass spectrometry (IM MS). The values of the theoretically predicted isomers were compared with the experimental CCS values to confirm their structures.

Understanding proton capture and cation-induced dimerization of [Ag(BDT)] clusters by ion mobility mass spectrometry.

Proton transfer reactions have been a topic of fundamental interest in several areas of chemistry and biology. However, such reactivity has not been explored in detail for nanoscale materials. In this article, we present a unique reaction of an atomically precise monolayer-protected silver nanocluster, [Ag(BDT)], with a proton (H).

AuIr(PET): An Unusual Alloy Cluster through Intercluster Reaction.

An intercluster reaction between Au(PET) and Ir(PET) producing the alloy cluster, AuIr(PET) exclusively, is demonstrated where the ligand PET is 2-phenylethanethiol. Typical reactions of this kind between Au(PET) and Ag(SR), and other clusters reported previously, produce mixed cluster products. The cluster composition was confirmed by detailed high-resolution electrospray ionization mass spectrometry (ESI MS) and other spectroscopic techniques.

Interaction of nucleobases with silicon doped and defective silicon doped graphene and optical properties.

The interaction of nucleobases (NBs) with the surface of silicon doped graphene (SiGr) and defective silicon doped graphene (dSiGr) has been studied using electronic structure methods. A systematic comparison of the calculated interaction energies (adsorption strength) of NBs with the surface of SiGr and dSiGr with those of pristine graphene (Gr) has also been made. The doping of graphene with silicon increases the adsorption strength of NBs.

Influence of the size and charge of gold nanoclusters on complexation with siRNA: a molecular dynamics simulation study.

The complexation of small interfering RNA (siRNA) with positively charged gold nanoclusters has been studied in the present investigation with the help of classical molecular dynamics and steered molecular dynamics simulations accompanied by free energy calculations. The results show that gold nanoclusters form a stable complex with siRNA. The wrapping of siRNA around the gold nanocluster depends on the size and charge on the surface of the gold cluster.