IP6, PF74 affect HIV-1 capsid stability through modulation of hexamer-hexamer tilt angle preference.

The HIV-1 capsid is an irregularly shaped protein complex containing the viral genome and several proteins needed for integration into the host cell genome. Small molecules, such as the drug-like compound PF-3450074 (PF74) and the anionic sugar inositolhexakisphosphate (IP6), are known to impact capsid stability, although the mechanisms through which they do so remain unknown. In this study, we employed atomistic molecular dynamics simulations to study the impact of molecules bound to hexamers at the central pore (IP6) and the FG-binding site (PF74) on the interface between capsid oligomers.

CosolvKit: a Versatile Tool for Cosolvent MD Preparation and Analysis.

Cosolvent molecular dynamics (MDs) are an increasingly popular form of simulations where small molecule cosolvents are added to water-solvated protein systems. These simulations can perform diverse target characterization tasks, including cryptic and allosteric pocket identification and pharmacophore profiling and supplement suites of enhanced sampling methods to explore protein conformational landscapes. The behavior of these systems is tied to the cosolvents used, so the ability to define diverse and complex mixtures is critical in dictating the outcome of the simulations.

IP6 and PF74 affect HIV-1 Capsid Stability through Modulation of Hexamer-Hexamer Tilt Angle Preference.

The HIV-1 capsid is an irregularly shaped complex of about 1200 protein chains containing the viral genome and several viral proteins. Together, these components are the key to unlocking passage into the nucleus, allowing for permanent integration of the viral genome into the host cell genome. Recent interest into the role of the capsid in viral replication has been driven by the approval of the first-in-class drug lenacapavir, which marks the first drug approved to target a non-enzymatic HIV-1 viral protein.

Reactive Docking: A Computational Method for High-Throughput Virtual Screenings of Reactive Species.

We describe the formalization of the reactive docking protocol, a method developed to model and predict reactions between small molecules and biological macromolecules. The method has been successfully used in a number of applications already, including recapitulating large proteomics data sets, performing structure-reactivity target optimizations, and prospective virtual screenings. By modeling a near-attack conformation-like state, no QM calculations are required to model the ligand and receptor geometries.

Performance evaluation of flexible macrocycle docking in AutoDock.

Macrocycles represent an important class of ligands, both in natural products and designed drugs. In drug design, macrocyclizations can impart specific ligand conformations and contribute to passive permeation by encouraging intramolecular H-bonds. AutoDock-GPU and Vina can model macrocyclic ligands flexibly, without requiring the enumeration of macrocyclic conformers before docking.

Ringtail: A Python Tool for Efficient Management and Storage of Virtual Screening Results.

Virtual screening using molecular docking is now routinely used for the rapid evaluation of very large ligand libraries in early stage drug discovery. As the size of compound libraries which can feasibly be screened grows, so do the challenges in result management and storage. Here we introduce Ringtail, a new Python tool in the AutoDock Suite for efficient storage and analysis of virtual screening data based on portable SQLite databases.

Benchmarking the Performance of Irregular Computations in AutoDock-GPU Molecular Docking.

Irregular applications can be found in different scientific fields. In computer-aided drug design, molecular docking simulations play an important role in finding promising drug candidates. AutoDock is a software application widely used for predicting molecular interactions at close distances.

COVID 19 repercussions in ophthalmology: a narrative review.

Background: The new coronavirus of 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally and has repercussions within ophthalmological care. It has caused ocular manifestations in some patients, which can spread through eye secretions.

Objectives: The purpose of this review was to summarize the currently available evidence on COVID-19 with regard to its implications for ophthalmology.

AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings.

AutoDock Vina is arguably one of the fastest and most widely used open-source programs for molecular docking. However, compared to other programs in the AutoDock Suite, it lacks support for modeling specific features such as macrocycles or explicit water molecules. Here, we describe the implementation of this functionality in AutoDock Vina 1.

Discovery of Potent Coumarin-Based Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains Using Structure-Based Design.

In immunoglobulin light-chain (LC) amyloidosis, transient unfolding or unfolding and proteolysis enable aggregation of LC proteins, causing potentially fatal organ damage. A drug that kinetically stabilizes LCs could suppress aggregation; however, LC sequences are variable and have no natural ligands, hindering drug development efforts. We previously identified high-throughput screening hits that bind to a site at the interface between the two variable domains of the LC homodimer.

Accelerating AutoDock4 with GPUs and Gradient-Based Local Search.

AutoDock4 is a widely used program for docking small molecules to macromolecular targets. It describes ligand-receptor interactions using a physics-inspired scoring function that has been proven useful in a variety of drug discovery projects. However, compared to more modern and recent software, AutoDock4 has longer execution times, limiting its applicability to large scale dockings.

A Strain-Specific Inhibitor of Receptor-Bound HIV-1 Targets a Pocket near the Fusion Peptide.

Disruption of viral fusion represents a viable, albeit under-explored, target for HIV therapeutics. Here, while studying the receptor-bound envelope glycoprotein conformation by cryoelectron microscopy (cryo-EM), we identify a pocket near the base of the trimer containing a bound detergent molecule and perform in silico drug screening by using a library of drug-like and commercially available molecules. After down-selection, we solve cryo-EM structures that validate the binding of two small molecule hits in very similar manners to the predicted binding poses, including interactions with aromatic residues within the fusion peptide.

GPU-Accelerated Drug Discovery with Docking on the Summit Supercomputer: Porting, Optimization, and Application to COVID-19 Research.

Protein-ligand docking is an in silico tool used to screen potential drug compounds for their ability to bind to a given protein receptor within a drug-discovery campaign. Experimental drug screening is expensive and time consuming, and it is desirable to carry out large scale docking calculations in a high-throughput manner to narrow the experimental search space. Few of the existing computational docking tools were designed with high performance computing in mind.

Initial Analysis of the Arylomycin D Antibiotics.

The arylomycins are a class of natural product antibiotics that inhibit bacterial type I signal peptidase and are under development as therapeutics. Four classes of arylomycins are known, arylomycins A-D. Previously, we reported the synthesis and analysis of representatives of the A, B, and C classes and showed that their spectrum of activity has the potential to be much broader than originally assumed.

Charting Hydrogen Bond Anisotropy.

A hydrogen bond (HB) is an essential interaction in countless phenomena, regulating the chemistry of life. HBs are characterized by two features, strength and directionality, with a high degree of heterogeneity across different chemical groups. These characteristics are dependent on the electronic configuration of the atoms involved in the interaction, which, in turn, is influenced strongly by the local molecular environment.

Structural basis for strand-transfer inhibitor binding to HIV intasomes.

The HIV intasome is a large nucleoprotein assembly that mediates the integration of a DNA copy of the viral genome into host chromatin. Intasomes are targeted by the latest generation of antiretroviral drugs, integrase strand-transfer inhibitors (INSTIs). Challenges associated with lentiviral intasome biochemistry have hindered high-resolution structural studies of how INSTIs bind to their native drug target.

D3R Grand Challenge 4: prospective pose prediction of BACE1 ligands with AutoDock-GPU.

In this paper we describe our approaches to predict the binding mode of twenty BACE1 ligands as part of Grand Challenge 4 (GC4), organized by the Drug Design Data Resource. Calculations for all submissions (except for one, which used AutoDock4.2) were performed using AutoDock-GPU, the new GPU-accelerated version of AutoDock4 implemented in OpenCL, which features a gradient-based local search.

Comparison of affinity ranking using AutoDock-GPU and MM-GBSA scores for BACE-1 inhibitors in the D3R Grand Challenge 4.

Molecular docking has been successfully used in computer-aided molecular design projects for the identification of ligand poses within protein binding sites. However, relying on docking scores to rank different ligands with respect to their experimental affinities might not be sufficient. It is believed that the binding scores calculated using molecular mechanics combined with the Poisson-Boltzman surface area (MM-PBSA) or generalized Born surface area (MM-GBSA) can predict binding affinities more accurately.

Mechanistic Pathway on Human α-Glucosidase Maltase-Glucoamylase Unveiled by QM/MM Calculations.

The excessive consumption of starch in human diets is associated with highly prevalent chronic metabolic diseases such as type 2 diabetes and obesity. α-Glucosidase enzymes contribute to the digestion of starch into glucose and are thus attractive therapeutic targets for diabetes. Given that the active sites of the various families of α-glucosidases have different sizes and structural features, atomistic descriptions of the catalytic mechanisms of these enzymes can support the development of potent and selective new inhibitors.

Use of biodegradable collagen-glycosaminoglycan copolymer matrix implant to reduce postoperative fibrosis in strabismus surgery.

The occurrence of restrictive strabismus after conjunctival surgeries is widely described in the literature. Fibrosis causes adherence of the conjunctiva to the Tenon's capsule, intermuscular membrane, adipose orbital tissue, sclera, and extraocular muscle tissue. Fibrosis causes adherence of the conjunctiva to the Tenon's capsule, intermuscular membrane, adipose orbital tissue, sclera, and extraocular muscle tissue.

Interaction with specific HSP90 residues as a scoring function: validation in the D3R Grand Challenge 2015.

Here is reported the development of a novel scoring function that performs remarkably well at identifying the native binding pose of a subset of HSP90 inhibitors containing aminopyrimidine or resorcinol based scaffolds. This scoring function is called PocketScore, and consists of the interaction energy between a ligand and three residues in the binding pocket: Asp93, Thr184 and a water molecule. We integrated PocketScore into a molecular docking workflow, and used it to participate in the Drug Design Data Resource (D3R) Grand Challenge 2015 (GC2015).

HMG-CoA Reductase inhibitors: an updated review of patents of novel compounds and formulations (2011-2015).

Statins are remarkably safe and efficient medications that are the mainstay of hypercholesterolemia treatment and have proven to be an invaluable tool to lower the risk of acute cardiovascular events. These compounds are inhibitors of 3-hydroxy-methylglutaryl CoA reductase (HMG-R), the rate-limiting enzyme in cholesterol biosynthesis. In spite of their success, they present undesirable side effects and are now loosing patent protection, which provides a great opportunity for the development of new and improved statins.