Computational aided acetaminophen - phthalic acid molecularly imprinted polymer design for analytical determination of known and new developed recreational drugs.

In recent times, abuse drug consumption rates have been increasing. In addition, authorities have detected a trend in the development of new substances expressly created to avoid legislation. These novel psychoactive substances (NPS) are non-registered formulations, closely chemically related to outlawed ones to maintain the same psychotropic effects while circumventing legal restrictions. This issue arises enormous social, sanitary, and road safety problems since there is no way to detect nor quantify these non-registered substances. The aim of this work is the development of a high selective material able to pre-concentrate and detect NPS. On that account, molecularly imprinted polymers (MIPs) designed with an imprinted cavity that matches the cathinones structural shape were proposed to detect both conventional and new cathinone derived recreational drugs. The increasing number of illicit drug modifications that is being reported requires developing a receptor valid for not only known molecules but also for incoming ones; thus, a virtual procedure must be carried out to take a step forward towards future modifications. Accordingly, a computational MIP design is proposed as the most appropriated method to effectively design this receptor. By means of molecular dynamics and molecular docking, several combinations are studied regarding their pre-polymerization complex stability but also their rebinding capacity against the proposed analytes. Hence, a phthalic acid - acetaminophen MIP is selected as the most well-suited receptor, valid for current and forthcoming cathinone recreational drugs.

OptiPharm: An evolutionary algorithm to compare shape similarity.

Virtual Screening (VS) methods can drastically accelerate global drug discovery processes. Among the most widely used VS approaches, Shape Similarity Methods compare in detail the global shape of a query molecule against a large database of potential drug compounds. Even so, the databases are so enormously large that, in order to save time, the current VS methods are not exhaustive, but they are mainly local optimizers that can easily be entrapped in local optima. It means that they discard promising compounds or yield erroneous signals. In this work, we propose the use of efficient global optimization techniques, as a way to increase the quality of the provided solutions. In particular, we introduce OptiPharm, which is a parameterizable metaheuristic that improves prediction accuracy and offers greater computational performance than WEGA, a Gaussian-based shape similarity method. OptiPharm includes mechanisms to balance between exploration and exploitation to quickly identify regions in the search space with high-quality solutions and avoid wasting time in non-promising areas. OptiPharm is available upon request via email.

Comparative studies on the inhibitory activities of selected benzoic acid derivatives against secretory phospholipase A2, a key enzyme involved in the inflammatory pathway.

Inflammation is considered to be a key factor in major diseases like cancer, Alzheimer's disease, Parkinson's disease, etc. For the past few decades, pharmaceutical companies have explored new effective medications against inflammation. As a part of their detailed studies, many drug targets and drugs have been introduced against inflammation. In the present study, the inhibiting capacities of selected benzoic acid derivatives like gallic acid, vannilic acid, syringic acid and protocatechuic acid against secretory phospholipase A2 (sPLA2), a major enzyme involved in the inflammatory pathway, have been investigated. The detailed in vitro, biophysical and in silico studies carried out on these benzoic acid derivatives revealed that all the selected compounds have a uniform mode of binding in the active site of sPLA2 and are inhibitory in micromolar concentrations. The study also focuses on the non-selective inhibitory activity of an NSAID, aspirin, against sPLA2.

In silico discovery of a compound with nanomolar affinity to antithrombin causing partial activation and increased heparin affinity.

The medical and socioeconomic relevance of thromboembolic disorders promotes an ongoing effort to develop new anticoagulants. Heparin is widely used as activator of antithrombin but incurs side effects. We screened a large database in silico to find alternative molecules and predicted d-myo-inositol 3,4,5,6-tetrakisphosphate (TMI) to strongly interact with antithrombin. Isothermal titration calorimetry confirmed a TMI affinity of 45 nM, higher than the heparin affinity (273 nM). Functional studies, fluorescence analysis, and citrullination experiments revealed that TMI induced a partial activation of antithrombin that facilitated the interaction with heparin and low affinity heparins. TMI improved antithrombin inhibitory function of plasma from homozygous patients with antithrombin deficiency with a heparin binding defect and also in a model with endothelial cells. Our in silico screen identified a new, non-polysaccharide scaffold able to interact with the heparin binding domain of antithrombin. The functional consequences of this interaction were experimentally characterized and suggest potential anticoagulant therapeutic applications.

Kerr constant of multi-subunit particles and semiflexible, wormlike chains.

A formalism is developed for the Kerr constant of particles composed of subunits whose electro-optical properties have axial symmetry. A protocol is devised for the calculation of the Kerr constant from the dipole moments and the electrical and optical polarizabilities of the subunits. The conformational average is required if the particle is flexible. Based on that formalism, the Kerr constant of semiflexible, wormlike chains is calculated with the help of a discrete version to which the previous formalism is applied. The required conformational averages are evaluated by means of Monte Carlo simulation. Thus we obtain expressions for the Kerr constant of wormlike particles over the whole range of conformations.

MULTIHYDRO and MONTEHYDRO: conformational search and Monte Carlo calculation of solution properties of rigid or flexible bead models.

A computer program, MULTIHYDRO, has been constructed for the calculation of hydrodynamic coefficients and other solution properties of multiple possible conformations of a bead model. With minimal additional programming to describe the model under study, this program interfaces efficiently with HYDRO for the calculation of solution properties, including hydrodynamic coefficients, radius of gyration, covolume, etc. A useful application is the conformation search of rigid macromolecules, because many possible conformations can be evaluated in a single run of the program. In this paper we also pay attention to the properties of flexible macromolecules, in the so-called Monte Carlo rigid-body approximation, which is virtually exact for the simpler solution properties. The theoretical aspects of the procedure are described, and we show how MULTIHYDRO can be employed for this calculation. However, for flexible molecules, a more general simulation scheme is importance-sampling Monte Carlo generation. We describe how this procedure is implemented in another computer program, MONTEHYDRO. Examples of the usage of these tools are provided.

Transient electric birefringence of wormlike macromolecules in electric fields of arbitrary strength: a computer simulation study.

We have studied the birefringence decay of linear models of macromolecules for two different types of flexibility, the broken-rod chain and the wormlike chain, using a computer simulation of a transient electric birefringence experiment. We have paid particular attention to the influence of the intensity of the orienting field, including two orienting mechanisms, the induced dipole, and the permanent dipole. We have compared wormlike and broken-rod models of the same radius of gyration, finding that they present a different decay curve under the influence of the same intensity of the field. We have seen that these differences are due to the faster relaxation times (smaller in the wormlike chain model) and amplitudes, because, regardless of the type of flexibility, the overall size of a molecule (measured by the radius of gyration) essentially determines the longest relaxation time. We have also analyzed how the relaxation process is affected by the degree of flexibility, the orientation mechanisms, and the intensity of the field. Studying a different aspect, we have paid attention to the deformation of a molecule in a transient electric birefringence experiment as a source of information. In this work we have developed equations to characterize this deformation in terms of one of the components of the gyration tensor, if a dynamic light scattering experiment under the influence of an electric field could be performed. To develop this work we have simulated the Brownian dynamics of the different models, relaxing after the removal of an orienting external electric field of arbitrary strength. A comparison with other methods such a the rigid body treatment or the correlation analysis of Brownian trajectories has also been included. We have seen that differences between the two Brownian dynamics methods are small and that the rigid-body treatment is only an acceptable approximation to obtain the longest relaxation time.

Calculation of the solution properties of flexible macromolecules: methods and applications.

While the prediction of hydrodynamic properties of rigid particles is nowadays feasible using simple and efficient computer programs, the calculation of such properties and, in general, the dynamic behavior of flexible macromolecules has not reached a similar situation. Although the theories are available, usually the computational work is done using solutions specific for each problem. We intend to develop computer programs that would greatly facilitate the task of predicting solution behavior of flexible macromolecules. In this paper, we first present an overview of the two approaches that are most practical: the Monte Carlo rigid-body treatment, and the Brownian dynamics simulation technique. The Monte Carlo procedure is based on the calculation of properties for instantaneous conformations of the macromolecule that are regarded as if they were instantaneously rigid. We describe how a Monte Carlo program can be interfaced to the programs in the HYDRO suite for rigid particles, and provide an example of such calculation, for a hypothetical particle: a protein with two domains connected by a flexible linker. We also describe briefly the essentials of Brownian dynamics, and propose a general mechanical model that includes several kinds of intramolecular interactions, such as bending, internal rotation, excluded volume effects, etc. We provide an example of the application of this methodology to the dynamics of a semiflexible, wormlike DNA.