Virtual Screening of Small Molecules Targeting BCL2 with Machine Learning, Molecular Docking, and MD Simulation.

This study aimed to identify potential BCL-2 small molecule inhibitors using deep neural networks (DNN) and random forest (RF), algorithms as well as molecular docking and molecular dynamics (MD) simulations to screen a library of small molecules. The RF model classified 61% (2355/3867) of molecules as 'Active'. Further analysis through molecular docking with Vina identified CHEMBL3940231, CHEMBL3938023, and CHEMBL3947358 as top-scored small molecules with docking scores of -11, -10.9, and 10.8 kcal/mol, respectively. MD simulations validated these compounds' stability and binding affinity to the BCL2 protein.

Physiologically-based pharmacokinetic modelling and dosing evaluation of gentamicin in neonates using PhysPK.

Each year, infections caused around the 25% of neonatal deaths. Early empirical treatments help to reduce this mortality, although optimized dosing regimens are still lacking. The aims were to develop and validate a gentamicin physiologically-based pharmacokinetic (PBPK) model and then potentially explore dosing regimens in neonates using pharmacokinetic and pharmacodynamic criteria. The PBPK model developed consisted of 2 flow-limited tissues: kidney and other tissues. It has been implemented on a new tool called PhysPK, which allows structure reusability and evolution as predictive engine in Model-Informed Precision Dosing (MIPD). Retrospective pharmacokinetic information based on serum levels data from 47 neonates with gestational age between 32 and 39 weeks and younger than one-week postnatal age were used for model validation. The minimal PBPK model developed adequately described the gentamicin serum concentration-time profile with an average fold error nearly 1. Extended interval gentamicin dosing regimens (6 mg/kg q36h and 6 mg/kg q48h for term and preterm neonates, respectively) showed efficacy higher than 99% with toxicity lower than 10% through Monte Carlo simulation evaluations. The gentamicin minimal PBPK model developed in PhysPK from literature information, and validated in preterm and term neonates, presents adequate predictive performance and could be useful for MIPD strategies in neonates.