MD-Ligand-Receptor: A High-Performance Computing Tool for Characterizing Ligand-Receptor Binding Interactions in Molecular Dynamics Trajectories.

Molecular dynamics simulation is a widely employed computational technique for studying the dynamic behavior of molecular systems over time. By simulating macromolecular biological systems consisting of a drug, a receptor and a solvated environment with thousands of water molecules, MD allows for realistic ligand-receptor binding interactions (lrbi) to be studied. In this study, we present MD-ligand-receptor (MDLR), a state-of-the-art software designed to explore the intricate interactions between ligands and receptors over time using molecular dynamics trajectories. Unlike traditional static analysis tools, MDLR goes beyond simply taking a snapshot of ligand-receptor binding interactions (lrbi), uncovering long-lasting molecular interactions and predicting the time-dependent inhibitory activity of specific drugs. With MDLR, researchers can gain insights into the dynamic behavior of complex ligand-receptor systems. Our pipeline is optimized for high-performance computing, capable of efficiently processing vast molecular dynamics trajectories on multicore Linux servers or even multinode HPC clusters. In the latter case, MDLR allows the user to analyze large trajectories in a very short time. To facilitate the exploration and visualization of lrbi, we provide an intuitive Python notebook (Jupyter), which allows users to examine and interpret the results through various graphical representations.

Molecular Dynamics Investigations of Human DNA-Topoisomerase I Interacting with Novel Dewar Valence Photo-Adducts: Insights into Inhibitory Activity.

Chronic exposure to ultraviolet (UV) radiation is known to induce the formation of DNA photo-adducts, including cyclobutane pyrimidine dimers (CPDs) and Dewar valence derivatives (DVs). While CPDs usually occur at higher frequency than DVs, recent studies have shown that the latter display superior selectivity and significant stability in interaction with the human DNA/topoisomerase 1 complex (TOP1). With the aim to deeply investigate the mechanism of interaction of DVs with TOP1, we report here four all-atom molecular dynamic simulations spanning one microsecond. These simulations are focused on the stability and conformational changes of two DNA/TOP1-DV complexes in solution, the data being compared with the biomimetic thymine dimer counterparts. Results from root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) analyses unequivocally confirmed increased stability of the DNA/TOP1-DV complexes throughout the simulation duration. Detailed interaction analyses, uncovering the presence of salt bridges, hydrogen bonds, water-mediated interactions, and hydrophobic interactions, as well as pinpointing the non-covalent interactions within the complexes, enabled the identification of specific TOP1 residues involved in the interactions over time and suggested a potential TOP1 inhibition mechanism in action.

Molecular Docking and Dynamics Simulation Revealed the Potential Inhibitory Activity of New Drugs against Human Topoisomerase I Receptor.

Human Topoisomerase I (hTop1p) is a ubiquitous enzyme that relaxes supercoiled DNA through a conserved mechanism involving transient breakage, rotation, and binding. Htop1p is the molecular target of the chemotherapeutic drug camptothecin (CPT). It causes the hTop1p-DNA complex to slow down the binding process and clash with the replicative machinery during the S phase of the cell cycle, forcing cells to activate the apoptotic response. This gives hTop1p a central role in cancer therapy. Recently, two artesunic acid derivatives (compounds c6 and c7) have been proposed as promising inhibitors of hTop1p with possible antitumor activity. We used several computational approaches to obtain in silico confirmations of the experimental data and to form a comprehensive dynamic description of the ligand-receptor system. We performed molecular docking analyses to verify the ability of the two new derivatives to access the enzyme-DNA interface, and a classical molecular dynamics simulation was performed to assess the capacity of the two compounds to maintain a stable binding pose over time. Finally, we calculated the noncovalent interactions between the two new derivatives and the hTop1p receptor in order to propose a possible inhibitory mechanism like that adopted by CPT.