Planning for steerable needles in neurosurgery

The increasing adoption of robotic-assisted surgery has opened up the possibility to control innovative dexterous tools to improve patient outcomes in a minimally invasive way. Steerable needles belong to this category, and their potential has been recognised in various surgical fields, including neurosurgery. However, planning for steerable catheters' insertions might appear counterintuitive even for expert clinicians. Strategies and tools to aid the surgeon in selecting a feasible trajectory to follow and methods to assist them intra-operatively during the insertion process are currently of great interest as they could accelerate steerable needles' translation from research to practical use. However, existing computer-assisted planning (CAP) algorithms are often limited in their ability to meet both operational and kinematic constraints in the context of precise neurosurgery, due to its demanding surgical conditions and highly complex environment. The research contributions in this thesis relate to understanding the existing gap in planning curved insertions for steerable needles and implementing intelligent CAP techniques to use in the context of neurosurgery. Among this thesis contributions showcase (i) the development of a pre-operative CAP for precise neurosurgery applications able to generate optimised paths at a safe distance from brain sensitive structures while meeting steerable needles kinematic constraints; (ii) the development of an intra-operative CAP able to adjust the current insertion path with high stability while compensating for online tissue deformation; (iii) the integration of both methods into a commercial user front-end interface (NeuroInspire, Renishaw plc.) tested during a series of user-controlled needle steering animal trials, demonstrating successful targeting performances. (iv) investigating the use of steerable needles in the context of laser interstitial thermal therapy (LiTT) for maesial temporal lobe epilepsy patients and proposing the first LiTT CAP for steerable needles within this context. The thesis concludes with a discussion of these contributions and suggestions for future work.Open Acces

On the development of B-Raf inhibitors acting through innovative mechanisms

B-Raf is a protein kinase participating to the regulation of many biological processes in cells. Several studies have demonstrated that this protein is frequently upregulated in human cancers, especially when it bears activating mutations. In the last years, few ATP-competitive inhibitors of B-Raf have been marketed for the treatment of melanoma and are currently under clinical evaluation on a variety of other types of cancer. Although the introduction of drugs targeting B-Raf has provided significant advances in cancer treatment, responses to ATP-competitive inhibitors remain limited, mainly due to selectivity issues, side effects, narrow therapeutic windows, and the insurgence of drug resistance. Impressive research efforts have been made so far towards the identification of novel ATP-competitive modulators with improved efficacy against cancers driven by mutant Raf monomers and dimers, some of them showing good promises. However, several limitations could still be envisioned for these compounds, according to literature data. Besides, increased attentions have arisen around approaches based on the design of allosteric modulators, polypharmacology, proteolysis targeting chimeras (PROTACs) and drug repurposing for the targeting of B-Raf proteins. The design of compounds acting through such innovative mechanisms is rather challenging. However, valuable therapeutic opportunities can be envisioned on these drugs, as they act through innovative mechanisms in which limitations typically observed for approved ATP-competitive B-Raf inhibitors are less prone to emerge. In this article, current approaches adopted for the design of non-ATP competitive inhibitors targeting B-Raf are described, discussing also on the possibilities, ligands acting through such innovative mechanisms could provide for the obtainment of more effective therapies

Refinement and rescoring of virtual screening results

High-throughput docking is an established computational screening approach in drug design. This methodology enables a rapid identification of biologically active hit compounds, providing an efficient and cost-effective complement or alternative to experimental high-throughput screenings. However, limitations inherent to the methodology make docking results inevitably approximate. Two major Achille’s heels include the use of approximated scoring functions and the limited sampling of the ligand-target complexes. Therefore, docking results require careful evaluation and further post-docking analyses. In this article, we will overview our approach to post-docking analysis in virtual screenings. BEAR (Binding Estimation After Refinement) was developed as a post-docking processing tool that refines docking poses by means of molecular dynamics (MD) and then rescores the ligands based on more accurate scoring functions (MM-PB(GB)SA). The tool has been validated and used prospectively in drug discovery applications. Future directions regarding refinement and rescoring in virtual screening are discussed

Computational polypharmacology comes of age

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Molecular docking: Shifting paradigms in drug discovery

Molecular docking is an established in silico structure-based method widely used in drug discovery. Docking enables the identification of novel compounds of therapeutic interest, predicting ligand-target interactions at a molecular level, or delineating structure-activity relationships (SAR), without knowing a priori the chemical structure of other target modulators. Although it was originally developed to help understanding the mechanisms of molecular recognition between small and large molecules, uses and applications of docking in drug discovery have heavily changed over the last years. In this review, we describe how molecular docking was firstly applied to assist in drug discovery tasks. Then, we illustrate newer and emergent uses and applications of docking, including prediction of adverse effects, polypharmacology, drug repurposing, and target fishing and profiling, discussing also future applications and further potential of this technique when combined with emergent techniques, such as artificial intelligence

Identification of Promising Drug Candidates against Prostate Cancer through Computationally-Driven Drug Repurposing

Prostate cancer (PC) is one of the most common types of cancer in males. Although early stages of PC are generally associated with favorable outcomes, advanced phases of the disease present a significantly poorer prognosis. Moreover, currently available therapeutic options for the treatment of PC are still limited, being mainly focused on androgen deprivation therapies and being characterized by low efficacy in patients. As a consequence, there is a pressing need to identify alternative and more effective therapeutics. In this study, we performed large-scale 2D and 3D similarity analyses between compounds reported in the DrugBank database and ChEMBL molecules with reported anti-proliferative activity on various PC cell lines. The analyses included also the identification of biological targets of ligands with potent activity on PC cells, as well as investigations on the activity annotations and clinical data associated with the more relevant compounds emerging from the ligand-based similarity results. The results led to the prioritization of a set of drugs and/or clinically tested candidates potentially useful in drug repurposing against PC

Chemoinformatics Analyses of Tau Ligands Reveal Key Molecular Requirements for the Identification of Potential Drug Candidates against Tauopathies

Tau is a highly soluble protein mainly localized at a cytoplasmic level in the neuronal cells, which plays a crucial role in the regulation of microtubule dynamic stability. Recent studies have demonstrated that several factors, such as hyperphosphorylation or alterations of Tau metabolism, may contribute to the pathological accumulation of protein aggregates, which can result in neuronal death and the onset of a number of neurological disorders called Tauopathies. At present, there are no available therapeutic remedies able to reduce Tau aggregation, nor are there any structural clues or guidelines for the rational identification of compounds preventing the accumulation of protein aggregates. To help identify the structural properties required for anti-Tau aggregation activity, we performed extensive chemoinformatics analyses on a dataset of Tau ligands reported in ChEMBL. The performed analyses allowed us to identify a set of molecular properties that are in common between known active ligands. Moreover, extensive analyses of the fragment composition of reported ligands led to the identification of chemical moieties and fragment combinations prevalent in the more active compounds. Interestingly, many of these fragments were arranged in recurring frameworks, some of which were clearly present in compounds currently under clinical investigation. This work represents the first in-depth chemoinformatics study of the molecular properties, constituting fragments and similarity profiles, of known Tau aggregation inhibitors. The datasets of compounds employed for the analyses, the identified molecular fragments and their combinations are made publicly available as supplementary material

Prediction of activity and selectivity profiles of human Carbonic Anhydrase inhibitors using machine learning classification models

The development of selective inhibitors of the clinically relevant human Carbonic Anhydrase (hCA) isoforms IX and XII has become a major topic in drug research, due to their deregulation in several types of cancer. Indeed, the selective inhibition of these two isoforms, especially with respect to the homeostatic isoform II, holds great promise to develop anticancer drugs with limited side effects. Therefore, the development of in silico models able to predict the activity and selectivity against the desired isoform(s) is of central interest. In this work, we have developed a series of machine learning classification models, trained on high confidence data extracted from ChEMBL, able to predict the activity and selectivity profiles of ligands for human Carbonic Anhydrase isoforms II, IX and XII. The training datasets were built with a procedure that made use of flexible bioactivity thresholds to obtain well-balanced active and inactive classes. We used multiple algorithms and sampling sizes to finally select activity models able to classify active or inactive molecules with excellent performances. Remarkably, the results herein reported turned out to be better than those obtained by models built with the classic approach of selecting an a priori activity threshold. The sequential application of such validated models enables virtual screening to be performed in a fast and more reliable way to predict the activity and selectivity profiles against the investigated isoforms