Molecular Docking Improved with Human Spatial Perception Using Virtual Reality.

Adaptive steered molecular dynamics (ASMD) is a computational biophysics method in which an external force is applied to a selected set of atoms or a specific reaction coordinate to induce a particular molecular motion. Virtual reality (VR) based methods for protein-ligand docking are beneficial for visualizing on-the-fly interactive molecular dynamics and performing promising docking trajectories. In this paper, we propose a novel method to guide ASMD with optimal trajectories collected from human experiences using interactive molecular dynamics in virtual reality (iMD-VR). We also explain the benefits of using VR as a tool for expediting the process of ligand binding, outlining an experimental protocol that enables iMD-VR users to guide Amprenavir into and out of the binding pockets of HIV-1 protease and recreate their respective crystallographic binding poses within 5 minutes. Later, we discuss our analysis of the results from iMD-VR-assisted ASMD simulation and assess its performance compared to a standard ASMD simulation. From the accuracy point of view, our proposed method calculates higher Potential Mean Force (PMF) values consistently relative to a standard ASMD simulation with an almost twofold increase in all the experiments. Finally, we describe the novelty of the research and discuss results showcasing a faster and more effective convergence of the ligand to the protein's binding site as compared to a standard molecular dynamics simulation, proving the effectiveness of VR in the field of drug discovery. Future work includes the development of an artificial intelligence algorithm capable of predicting optimal binding trajectories for many protein-ligand pairs, as well as the required force needed to steer the ligand to follow the said trajectory.

Calcium-induced structural transitions are central to the folding, function, and processing of serratiopeptidase zymogen into mature form.

Serratia marcescens is an emerging health-threatening, gram-negative opportunistic pathogen associated with a wide variety of localized and life-threatening systemic infections. One of the most crucial virulence factors produced by S. marcescens is serratiopeptidase, a 50.2-kDa repeats-in-toxin (RTX) family broad-specificity zinc metalloprotease. RTX family proteins are functionally diverse exoproteins of gram-negative bacteria that exhibit calcium-dependent structural dynamicity and are secreted through a common type-1 secretion system (T1SS) machinery. To evaluate the impact of various divalent ligands on the folding and maturation of serratiopeptidase zymogen, the protein was purified and a series of structural and functional investigations were undertaken. The results indicate that calcium binding to the C-terminal RTX domain acts as a folding switch, triggering a disordered-to-ordered transition in the enzyme's conformation. Further, the auto-processing of the 16-amino acid N-terminal pro-peptide results in the maturation of the enzyme. The binding of calcium ions to serratiopeptidase causes a highly cooperative conformational transition in its structure, which is essential for the enzyme's activation and maturation. This conformational change is accompanied by an increase in solubility and enzymatic activity. For efficient secretion and to minimize intracellular toxicity, the enzyme needs to be in an unfolded extended form. The calcium-rich extracellular environment favors the folding and processing of zymogen into mature serratiopeptidase, i.e., the holo-form required by S. marcescens to establish infections and survive in different environmental niches.

Anticancer mechanisms of ß-carbolines.

ß-Carboline nucleus is therapeutically valuable in medicinal chemistry for the treatment of varied number of diseases, most importantly cancer. The potent and wide-ranging activity of ß-carboline has established them as imperative pharmacological scaffolds especially in the cancer treatment. Numerous derivatives such as Tetrahydro ß-carbolines, metal complexed ß-carbolines, mono, di and tri substituted ß-carbolines have been reported to possess dynamic anticancer activity. These different substituted ß-carboline derivatives had shown different mechanism of action and plays important role in anticancer drug discovery and development. The review is an update of the chemistry of ß-carbolines, both synthetic and natural origin acting through various targets against cancerous cells. In addition to this, studies of multitarget molecules designed by coupling ß-carbolines along with other mechanisms for treatment of neoplasm are also summarized.