Computational Intelligence in Drug Development

Table of Contents

1. Frontmatter

2. Virtual Screening of Drug Candidates for Repositioning for the Treatment of Parkinson’s Disease

   Anderson Luiz Pena da Costa, Henrique de Barros Lima, Mariana Pegrucci Barcelos, Carlos Henrique Tomich de Paula da Silva, Gabrieli Santos Oliveira, Carlton Anthony Taft, Lorane Izabel da Silva Hage-Melim

   Abstract

   MAO-B plays a key role in Parkinson’s disease by breaking down dopamine, leading to its depletion and contributing to oxidative stress in the brain. Thus, MAO-B inhibition helps preserve dopamine levels, improving motor symptoms and the quality of life for individuals with this neurodegenerative disease. This research aimed to identify known drugs with potential inhibitory activity against MAO-B through computational methods, prospecting their repositioning for Parkinson’s disease treatment. The methodological approach involved a multi-step process, beginning with the search for MAO-B inhibitors in BindingDB using the descriptor “Monoamine Oxidase B Inhibitor” and filtering for compounds with IC50 values up to 1.00 nM. These compounds were then subjected to molecular docking using the GOLD program, with MAO-B crystallographic data from the Protein Data Bank 3PO7, validated through redocking. The pharmacokinetic and toxicological properties of the selected compounds were assessed using QikProp (Schrödinger) and DEREK (Lhasa). In the final stage, drug repositioning was conducted by searching for chemical analogs of the best-performing compounds using the SwissSimilarity webserver. The goal was to identify promising drug candidates with pharmacokinetics suitable for oral administration and central nervous system distribution, as predicted by SwissADME and molecular docking analysis, using rasagiline, safinamide, and selegiline as reference drugs. The first stage of the research identified 3-methyl-8-(4,4,4-trifluorobutoxy)indeno[1,2-c]pyridazin-5-one as a promising candidate for Parkinson’s disease treatment due to its low IC50 (0.0140 nM), favorable predicted pharmacokinetic parameters, and absence of toxicological alerts. Additionally, the similarity-based search using this compound led to the identification of trifluperidol and leflunomide as promising candidates for drug repositioning in Parkinson’s disease treatment. The results obtained align with previous in silico and in vivo studies. Although this study did not identify novel candidates for drug repositioning, its methodology proved effective in screening publicly available chemical spaces for potential therapeutics. This approach may also be valuable for identifying compounds with therapeutic potential for diseases beyond Parkinson’s disease.

3. Molecular Dynamics Study and Prediction of Oral Toxicity of Calebin A in Alzheimer’s Disease

   Franciane Nunes de Souza, Gabrieli Santos Oliveira, Abraão Guimarães Silva, Leonardo Bruno Federico, Carlos H. T. P. Silva, Carlton A. Taft, Lorane Izabel da Silva Hage-Melim

   Abstract

   Alzheimer’s Disease (AD) is characterized by neurodegenerative changes that lead to the emergence of symptoms such as memory loss, difficulties in speaking, performing daily tasks, among others. The pathophysiology of AD is complex, but in general, its onset is related to the formation of neurofibrillary tangles and senile plaques; and some studies also report a link with neuroinflammatory processes and oxidative stress. Acetylcholinesterase (AChE) is an important pharmacological target due to its role in the pathophysiology of AD, as is the enzyme nitric oxide synthase (iNOS), which also contributes to the development and progression of the disease. The treatments available for AD only aim to delay the symptoms and improve quality of life, as there is no cure. In this context, because they contain substances that act synergistically against multiple molecular targets, overcoming various disadvantages, natural products are shown to be good alternatives for use in the planning of drugs for the treatment of neurodegenerative diseases. In addition, the use of computational methods is an important approach to overcoming the limitations imposed by traditional experimental methods. In view of this, this study aimed to use molecular dynamics simulations and in silico lethal dose assessment to help better understand the conformational behavior of the natural product calebin A and identify potential toxicological risks. GROMACS (GROningen MAchine for Chemical Simulation) software version 2020 and ProTox 3.0 were used for this purpose. The results of the interactions between Calebin A and AChE showed that the values are within the acceptable range 1–3 Å, without major disturbances. In the simulation between the compound and iNOS, it is possible to note that the complex remained stable during its time in the active site. The predicted LD₅₀ value is considered to be slightly toxic and is considered safe at low doses. It is hoped that these results will contribute to the planning of drugs for the treatment of Alzheimer’s disease.

4. GPR119 Promising Ligands: A Computational Analysis of New Strategies Against Type 2 Diabetes Mellitus

   Luiz Felipe M. A. Benicio, Érica C. M. Nascimento, João Batista Lopes Martins

   Abstract

   For the multifactorial disease Type 2 diabetes mellitus (T2DM), the main risk factors include aging, a sedentary lifestyle, inadequate diets, and obesity. It is recognized as a chronic metabolic syndrome, and has shown a steady increase in prevalence since the 1990s. Therefore, we performed two- and three-dimensional structural analyses of GPR119 using four PDB structures. G protein-coupled receptor 119 (GPR119) is considered a promising pharmacological target. Then, we used molecules with activity described in the literature with GPR119 for the prediction of pharmacokinetic and toxicological descriptors (ADMET). Docking study of these molecules were calculated with the crystallographic structures of GPR119 to analyze the interaction pattern with key residues. The data obtained from ADMET and docking of these studied molecules were correlated using the heatmap technique.

5. Beyond Healing: Aloe Vera’s Therapeutic Properties and Potential Drug Interactions

   Marcela Gonçalves Adriano, Luiza Stábile de Oliveira, Atala Melissa Ariño Rezende, Laila Youssef, Isabella Moreira Carneiro, Luís Felipe Rosa Costa, Carlton Anthony Taft, Vinicius Barreto da Silva

   Abstract

   Aloe vera is a medicinal plant renowned for its diverse therapeutic properties, including anti-inflammatory, antioxidant, antimicrobial, wound-healing, and antidiabetic effects. Its bioactive compounds, such as anthraquinones (e.g., aloin, aloe-emodin) and polysaccharides (e.g., acemannan), contribute to its efficacy in treating digestive disorders, diabetes, skin conditions, cardiovascular diseases, and even cancer. However, the concomitant use of Aloe vera with conventional medications raises concerns about herb-drug interactions, particularly those involving the cytochrome P450 (CYP450) enzyme system. Key compounds like aloe-emodin and emodin can inhibit CYP1A2 and CYP3A4, potentially altering the metabolism of drugs such as clopidogrel and methadone, leading to toxicity or even therapeutic failure depending on the drug affected. This chapter highlights the dual role of Aloe vera as both a therapeutic agent and a source of potential drug interactions, emphasizing the need for careful clinical monitoring to ensure safe and effective use in polypharmacy regimens.

6. New Cannabinoid-Derived Ligands with Potential Inhibitory Effects on Human Acetylcholinesterase (hAChE): An In-Silico Study

   Letícia de A. Nascimento, Érica C. M. Nascimento, João B. L. Martins

   Abstract

   Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) are three major neurodegenerative diseases characterized by the progressive loss of neuronal function in the brain. Both disorders have no cure, only palliative treatment aimed at improving the well-being of the patients. For this reason, the interest in searching for new alternatives with possible potential therapeutic activity has become paramount. An example of these innovations is the cannabinoid receptors, which have neuroprotective functions and are coupled to G proteins in the brain and peripheral tissues, named CB₁ and CB₂. Thus, in this study, a series of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) derivatives were developed in silico individually and complexed with the target protein human acetylcholinesterase as candidate proposals for the treatment of Alzheimer’s and Parkinson’s disease.

7. Therapeutic Peptides: Innovation and Potential at the Frontier of Medicine and Pharmacology

   Mariana Pegrucci Barcelos, Beatriz Brambila, Maria Teresa Marques Novo-Mansur, Carlos Henrique Tomich de Paula da Silva

   Abstract

   Therapeutic peptides have emerged as a powerful class of bioactive molecules with significant potential in the treatment of a wide range of diseases. Unlike traditional small molecules and monoclonal antibodies, peptides offer unique advantages such as a smaller size, enhanced tissue penetration, and easier chemical modification, while still maintaining high specificity and selectivity for a wide range of molecular targets. This chapter explores the key properties and mechanisms of action of therapeutic peptides, highlighting their role in modern pharmacology. It delves into the challenges associated with their development, such as stability, bioavailability, and immunogenicity, while also examining the latest advances in peptide synthesis and design. Additionally, the chapter showcases the therapeutic applications of peptides in the treatment of autoimmune diseases, cancer, diabetes, neurodegenerative disorders, and more. By examining the latest technological innovations, including nanotechnology and artificial intelligence, this work discusses the future opportunities and challenges in advancing peptide-based therapies. Ultimately, this chapter emphasizes the transformative potential of therapeutic peptides in the field of medicine, offering a glimpse into the next generation of targeted, personalized therapies.

8. Computational Approaches in the Development of Tubulin-Targeted Anticancer Agents

   Natália Bianca Puglia Conde, Carlos Henrique Tomich de Paula da Silva

   Abstract

   Solid tumours, as cancer, continue to be one of the main diseases with the highest incidence worldwide, with therapeutic obstacles resulting from pharmacokinetic difficulties. The structural protein tubulin, essential for cell replication, acts as a validated drug target. However, issues such as resistance to treatment and adverse effects require improved therapeutic compounds. Digital modelling techniques, which encompass ligand–protein interaction analysis, atomic motion simulations, and 3D pharmacophore mapping, have transformed pharmaceutical research into drug design. These approaches predict molecular commitments in precise receptor regions (including binding pockets of taxoids and vinca alkaloids), refining molecular attraction and target specificity. Particle behaviour modelling assesses complex durability, while structure–activity correlation structures direct molecular refinements. Therefore, virtual protein structure analysis and in silico laboratory testing methodologies are essential for confirming possible treatments by targeting the drug to the region in the body that needs to be targeted.

9. Enzymes as Targets for Disease Control: From Discovery to Application

   Beatriz Brambila, Ana Carolina Franco Severo Martelli, Ana Elisa Moraes Rosa, Mariana Pegrucci Barcelos, Solange Cristina Antão, André Vessoni Alexandrino, Carlos Henrique Tomich de Paula da Silva, Maria Teresa Marques Novo-Mansur

   Abstract

   Enzymes play crucial roles in the catalysis of biochemical reactions, facilitating and regulating essential metabolic pathways in living organisms. Given their important functions, enzymes are outstanding targets for the development of inhibitory compounds aimed at disease control. In addition, many pathogenic organisms often rely on enzymes for colonization, survival, and adaptation within the host environment, using them as virulence factors that contribute to disease progression by disrupting the host's immune mechanisms. The discovery of enzyme inhibitors can be based on in silico approaches, such as structure- or ligand-based virtual screening, which allow the identification of potential compounds by predicting interactions between enzymes and candidate molecules stored in specific databases. To evaluate inhibitor efficacy in biological systems and validate computational findings, enzymatic assays involving techniques such as colorimetry and fluorescence can be applied. Thus, this chapter aims to elucidate the main mechanisms of enzyme action and their roles in the survival and virulence of pathogenic organisms, highlighting their relevance in the development of inhibitory compounds targeting both pathogen- and host-derived enzymes for disease control, as well as the key tools employed in this process.

10. α-d-Phosphoglucomutase: A Promising Target in Carbohydrate Formation

    Gabriel Alves De Jong, Carlos Henrique Tomich de Paula da Silva

    Abstract

    In the context of drug discovery, many promising biological targets have been studied. In particular, enzymes have been identified as playing a central role in a wide range of diseases. Enzyme inhibition has been used for therapeutic intervention aimed at mitigating disease effects in humans, animals and plants. Upon selecting an enzyme of interest, the researcher explores its mechanism and metabolic role, analyzes its protein sequence and structure, and reviews the literature for evidence of its involvement in pathogenicity. Herein, phosphoglucomutase (PGM) was chosen for a mechanism overview, multiple sequence alignment, phylogenetic tree analysis, and structural search in Protein Data Bank (PDB). Lastly, we investigate reports of PGM expression in a diversity of pathogens.