Vinicius Barreto da Silva

Current topics in computer‐aided drug design

The addition of computer-aided drug design (CADD) technologies to the research and drug discovery approaches could lead to a reduction of up to 50% in the cost of drug design. Designing a drug is the process of finding or creating a molecule which has a specific activity on a biological organism. Development and drug discovery is a time-consuming, expensive, and interdisciplinary process whereas scientific advancements during the past two decades have altered the way pharmaceutical research produces new bioactive molecules. Advances in computational techniques and hardware solutions have enabled in silico methods to speed up lead optimization and identification. We will review current topics in computer-aided molecular design underscoring some of the most recent approaches and interdisciplinary processes. We will discuss some of the most efficient pathways and design.

Computer-aided drug design and ADMET predictions for identification and evaluation of novel potential farnesyltransferase inhibitors in cancer therapy

We have used various computational methodologies including molecular dynamics, density functional theory, virtual screening, ADMET predictions and molecular interaction field studies to design and analyze four novel potential inhibitors of farnesyltransferase (FTase). Evaluation of two proposals regarding their drug potential as well as lead compounds have indicated them as novel promising FTase inhibitors, with theoretically interesting pharmacotherapeutic profiles, when compared to the very active and most cited FTase inhibitors that have activity data reported, which are launched drugs or compounds in clinical tests. One of our two proposals appears to be a more promising drug candidate and FTase inhibitor, but both derivative molecules indicate potentially very good pharmacotherapeutic profiles in comparison with Tipifarnib and Lonafarnib, two reference pharmaceuticals. Two other proposals have been selected with virtual screening approaches and investigated by us, which suggest novel and alternatives scaffolds to design future potential FTase inhibitors. Such compounds can be explored as promising molecules to initiate a research protocol in order to discover novel anticancer drug candidates targeting farnesyltransferase, in the fight against cancer.

Psoralen and Bergapten: In Silico Metabolism and Toxicophoric Analysis of Drugs Used to Treat Vitiligo

PURPOSE To discuss the contribution of psoralen and bergapten metabolites on psoralens toxicity. METHODS Computational chemistry prediction of metabolic reactions and toxicophoric groups based on the expert systems Derek and Meteor. RESULTS a total of 15 metabolites were suggested for both psoralen and bergapten based on phase 1 and 2 biotransformations until the 3rd generation. Five toxicophoric substructures were shared among psoralen, bergapten and their corresponding metabolites; one toxicophoric marker (resorcinol) was only identified in bergapten and its biotransformation products. CONCLUSION Although the toxic effects of psoralens are well known and documented, there is little information concerning the role of their metabolites in this process. We believe this work add to the knowledge of which molecular substructures are relevant to the process of metabolism and toxicity induction, thus guiding the search and development of more effective and less toxic drugs to treat vitiligo.

Molecular dynamics, density functional, ADMET predictions, virtual screening, and molecular interaction field studies for identification and evaluation of novel potential CDK2 inhibitors in cancer therapy.

In this work, we have used molecular dynamics, density functional theory, virtual screening, ADMET predictions, and molecular interaction field studies to design and propose eight novel potential inhibitors of CDK2. The eight molecules proposed showed interesting structural characteristics that are required for inhibiting the CDK2 activity and show potential as drug candidates for the treatment of cancer. The parameters related to the Rule of Five were calculated, and only one of the molecules violated more than one parameter. One of the proposals and one of the drug-like compounds selected by virtual screening indicated to be promising candidates for CDK2-based cancer therapy.

COMPUTER-AIDED MOLECULAR DESIGN OF NOVEL HMG-CoA REDUCTASE INHIBITORS FOR THE TREATMENT OF HYPERCHOLESTEROLEMIA

Elevated cholesterol levels are a primary risk factor for the development of coronary artery disease. Dietary changes associated with drug therapy can reduce high serum cholesterol levels and dramatically decrease the risk of stroke and overall mortality. HMG-CoA reductase is an important molecular target of hypolipemic drugs, known as statins, which are effective in the reduction of cholesterol serum levels, attenuating cholesterol synthesis in-liver by competitive inhibition regarding the substrate HMG-CoA. In this paper, we have focused on computer-aided molecular design using density functional theory, flexible docking, molecular dynamics as well as ADME, and synthetic accessibility analyses in order to propose novel potential HMG-CoA reductase inhibitors, designed by bioisosteric modifications which are promising for the treatment of hypercholesterolemia.

Toxicophoric and Metabolic In Silico Evaluation of Benzimidazole and Phenylbenzamide Derivatives with Potential Application as Anticancer Agents

Poor pharmacokinetics and toxicity are responsible for most drug candidate failures. In order to attempt to some degree of ADMET (Absorption, Distribution, Metabolism, Excrection and Toxicity) information, in silico predictions arise currently as an interesting alternative to evaluate prototypes during early stages of the drug design processes, especially for anticancer candidates that constitute a class of therapeutic agents that exhibit substantial toxicity. A benzimidazole and a phenylbenzamide derivatives, previously identified as novel anticancer lead compounds able to prevent DNA binding to hnRNP K protein, were evaluated in silico regarding their metabolic profile and toxicity potential in order to give insights to the design of drug candidates with an adequate pharmaceutical profile. Considering the structure of proposed metabolites for both molecules, the phenylbenzamide derivative seems to be a molecule with better pharmaceutic profile, since its possible metabolites present a milder degree of chemical structure toxic alerts than the benzimidazole derivative that can cause chromosome damage induced by the benzimidazole group. It would be desirable during optimization of the phenylbenzamide derivative to maintain these characteristics during generation of analogues with substituents that are not known as potent toxicophoric groups. For the benzimidazole derivative, if the toxic events are really severe as it seems, one possible strategy would be replace the benzimidazole ring system by bioisosteres with lower toxic potential, hoping to maintain or enhance biological activity.

Cubebin and derivatives as inhibitors of mitochondrial complex I. Proposed interaction with subunit B8

The effects on mitochondrial respiration and complex I NADH oxidase activity of cubebin and derivatives were evaluated. The compounds inhibited the state 3 glutamate/malate-supported respiration of hamster liver mitochondria with IC50 values ranging from 12.16 to 83.96 μM. NADH oxidase reaction was evaluated in submitochondrial particles. The compounds also inhibited this activity, showing the same order of potency observed for effects on state 3 respiration, as well as a tendency towards a non-competitive type of inhibition (KI values ranging from 0.62 to 16.1 μM). A potential binding mode of these compounds with complex I subunit B8, assessed by docking calculations, is proposed.

Pharmacophore-based Drug Design of Novel Potential Tau Ligands for Alzheimer's Disease Treatment

An intracellular hallmark of Alzheimer Disease (AD) is accumulation of hyperphosphorylated tau as tangles of paired helical filaments (PHF). A significant advance in understanding taus behaviour isolated came when it was recognized that the protein contains isolated short peptide motifs, embedded in an otherwise hydrophilic environment, which have a high tendency for beta-structure and aggregation, forming the core of the PHF. In a recent work, we used the smallest fragment responsible for aggregation, the hexapeptide 306 VQIVYK 311 , in order to investigate with molecular dynamics simulations possible binding modes of the tau protein fragment with respect to an active flavonoid, which would be responsible for the inhibitory process of aggregation of tau. Considering such results, we have used in this work a selected pharmacophoric model and carried out a pharmacophore-based virtual screening with the purpose of designing novel potential Tau aggregation inhibitors. An initial set of 96 compounds was selected, of which 86 are unpublished regarding Tau anti-aggregation activity and the other 10 compounds are reported as Tau ligands. Prediction of biological activity and pharmaceutical properties indicated four tiophene derivatives as promising Tau aggregation inhibitors for Alzheimers disease treatment.

Novel aryl β-aminocarbonyl derivatives as inhibitors of Trypanosoma cruzi trypanothione reductase: binding mode revised by docking and GRIND2-based 3D-QSAR procedures

Trypanothione reductase has long been investigated as a promising target for chemotherapeutic intervention in Chagas disease, since it is an enzyme of a unique metabolic pathway that is exclusively present in the pathogen but not in the human host, which has the analog Glutathione reductase. In spite of the present data-set includes a small number of compounds, a combined use of flexible docking, pharmacophore perception, ligand binding site prediction, and Grid-Independent Descriptors GRIND2-based 3D-Quantitative Structure-Activity Relationships (QSAR) procedures allowed us to rationalize the different biological activities of a series of 11 aryl β-aminocarbonyl derivatives, which are inhibitors of Trypanosoma cruzi trypanothione reductase (TcTR). Three QSAR models were built and validated using different alignments, which are based on docking with the TcTR crystal structure, pharmacophore, and molecular interaction fields. The high statistical significance of the models thus obtained assures the robustness of this second generation of GRIND descriptors here used, which were able to detect the most important residues of such enzyme for binding the aryl β-aminocarbonyl derivatives, besides to rationalize distances among them. Finally, a revised binding mode has been proposed for our inhibitors and independently supported by the different methodologies here used, allowing further optimization of the lead compounds with such combined structure- and ligand-based approaches in the fight against the Chagas disease.

Search for a platelet-activating factor receptor in the Trypanosoma cruzi proteome: a potential target for Chagas disease chemotherapy

Chagas disease (CD) causes the highest burden of parasitic diseases in the Western Hemisphere and is therefore a priority for drug research and development. Platelet-activating factor (PAF) causes the CD parasite Trypanosoma cruzi to differentiate, which suggests that the parasite may express PAF receptors. Here, we explored the T. cruzi proteome for PAF receptor-like proteins. From a total of 23,000 protein sequences, we identified 29 hypothetical proteins that are predicted to have seven transmembrane domains (TMDs), which is the main characteristic of the G protein-coupled receptors (GPCRs), including the PAF receptor. The TMDs of these sequences were independently aligned with domains from 25 animal PAF receptors and the sequences were analysed for conserved residues. The conservation score mean values for the TMDs of the hypothetical proteins ranged from 31.7-44.1%, which suggests that if the putative T. cruzi PAF receptor is among the sequences identified, the TMDs are not highly conserved. These results suggest that T. cruzi contains several GPCR-like proteins and that one of these GPCRs may be a PAF receptor. Future studies may further validate the PAF receptor as a target for CD chemotherapy.