Multiscale MD simulations of wild-type and sickle hemoglobin aggregation.

Sickle cell disease is a hemoglobinopathy resulting from a point mutation from glutamate to valine at position six of the β-globin chains of hemoglobin. This mutation gives rise to pathological aggregation of the sickle hemoglobin and, as a result, impaired oxygen binding, misshapen and short-lived erythrocytes, and anemia. We aim to understand the structural effects caused by the single Glu6Val mutation leading to protein aggregation.

Dataset of AMBER force field parameters of drugs, natural products and steroids for simulations using GROMACS.

We provide general AMBER force field (GAFF) parameters for 160 organic molecules including drugs, natural products, and steroids, which can be employed without further processing in molecular dynamics (MD) simulations using GROMACS. We determined these parameters based on quantum mechanical (QM) calculations involving geometry optimization at the HF6-31G* level of theory. For each molecule we provide a coordinate file of the three-dimensional molecular structure, the topology and the parameter file.

High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2.

We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CL of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. From our screening of over one million compounds including approved drugs, investigational drugs, natural products, and organic compounds, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective 3CL inhibitors. Importantly, some of the identified compounds had previously been reported to exhibit inhibitory activities against the 3CL enzyme of the closely related SARS-CoV virus.

Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease.

Sickle cell disease (SCD) is a group of inherited disorders affecting red blood cells, which is caused by a single mutation that results in substitution of the amino acid valine for glutamic acid in the sixth position of the β-globin chain of hemoglobin. These mutant hemoglobin molecules, called hemoglobin S, can polymerize upon deoxygenation, causing erythrocytes to adopt a sickled form and to suffer hemolysis and vaso-occlusion. Until recently, only two drug therapies for SCD, which do not even fully address the manifestations of SCD, were approved by the United States (US) Food and Drug Administration.

Structural Basis of Antisickling Effects of Selected FDA Approved Drugs: A Drug Repurposing Study.

Introduction: Sickle cell disease is characterized by a point mutation involving substitution of glutamic acid at position 6 to valine. Encoded in this hydrophobic mutation is both an intrinsic capacity for the beta globin molecules to assemble into thermodynamically favoured polymeric states as well as a rational way of interrupting the aggregation.

Methods: In this work, starting with a theoretical model that employs occlusive binding onto the beta globin aggregation surface and using a range of computational methods and an effective energy for screening, a number of FDA approved drugs with computed aggregation inhibitory activities were identified.

Computational Analysis of Physicochemical Factors Driving CYP2D6 Ligand Interaction.

Background: The metabolic action of CYP2D6 remains a crucial factor influencing the therapeutic outcomes for many drug molecules while others are either only slightly affected or not affected altogether.

Objective: This study seeks to understand, atomistic resolution, the structural and physicochemical factors influencing CYP2D6 metabolic discrimination.

Method: Explicit solvent molecular dynamics simulations in GROMACS were employed to probe the conformational dynamics of CYP2D6 following which the most populated structures were employed for ligand interaction docking studies with AutoDock Vina using selected CYP2D6 drug substrates.