Riluzole-Rasagiline Hybrids: Toward the Development of Multi-Target-Directed Ligands for Amyotrophic Lateral Sclerosis

Polypharmacology is a new trend in amyotrophic lateral sclerosis (ALS) therapy and an effective way of addressing a multifactorial etiology involving excitotoxicity, mitochondrial dysfunction, oxidative stress, and microglial activation. Inspired by a reported clinical trial, we converted a riluzole (1)-rasagiline (2) combination into single-molecule multi-target-directed ligands. By a ligand-based approach, the highly structurally integrated hybrids 3-8 were designed and synthesized. Through a target- and phenotypic-based screening pipeline, we identified hit compound 6. It showed monoamine oxidase A (MAO-A) inhibitory activity (IC50 = 6.9 mu M) rationalized by in silico studies as well as in vitro brain permeability. By using neuronal and non-neuronal cell models, including ALS-patient-derived cells, we disclosed for 6 a neuroprotective/neuroinflammatory profile similar to that of the parent compounds and their combination. Furthermore, the unexpected MAO inhibitory activity of 1 (IC50 = 8.7 mu M) might add a piece to the puzzle of its anti-ALS molecular profile

Progress and Research Needs of Plant Biomass Degradation by Basidiomycete Fungi

Peer reviewe

The Oldest Case of Decapitation in the New World (Lapa do Santo, East-Central Brazil)

We present here evidence for an early Holocene case of decapitation in the New World (Burial 26), found in the rock shelter of Lapa do Santo in 2007. Lapa do Santo is an archaeological site located in the Lagoa Santa karst in east-central Brazil with evidence of human occupation dating as far back as 11.7-12.7 cal kyBP (95.4% interval). An ultra-filtered AMS age determination on a fragment of the sphenoid provided an age range of 9.1-9.4 cal kyBP (95.4% interval) for Burial 26. The interment was composed of an articulated cranium, mandible and first six cervical vertebrae. Cut marks with a v-shaped profile were observed in the mandible and sixth cervical vertebra. The right hand was amputated and laid over the left side of the face with distal phalanges pointing to the chin and the left hand was amputated and laid over the right side of the face with distal phalanges pointing to the forehead. Strontium analysis comparing Burial 26's isotopic signature to other specimens from Lapa do Santo suggests this was a local member of the group. Therefore, we suggest a ritualized decapitation instead of trophy-taking, testifying for the sophistication of mortuary rituals among hunter-gatherers in the Americas during the early Archaic period. In the apparent absence of wealth goods or elaborated architecture, Lapa do Santo's inhabitants seemed to use the human body to express their cosmological principles regarding death

Exploring the RNA-Recognition Mechanism Using Supervised Molecular Dynamics (SuMD) Simulations: Toward a Rational Design for Ribonucleic-Targeting Molecules?

Although proteins have represented the molecular target of choice in the development of new drug candidates, the pharmaceutical importance of ribonucleic acids has gradually been growing. The increasing availability of structural information has brought to light the existence of peculiar three-dimensional RNA arrangements, which can, contrary to initial expectations, be recognized and selectively modulated through small chemical entities or peptides. The application of classical computational methodologies, such as molecular docking, for the rational development of RNA-binding candidates is, however, complicated by the peculiarities characterizing these macromolecules, such as the marked conformational flexibility, the singular charges distribution, and the relevant role of solvent molecules. In this work, we have thus validated and extended the applicability domain of SuMD, an all-atoms molecular dynamics protocol that allows to accelerate the sampling of molecular recognition events on a nanosecond timescale, to ribonucleotide targets of pharmaceutical interest. In particular, we have proven the methodological ability by reproducing the binding mode of viral or prokaryotic ribonucleic complexes, as well as that of artificially engineered aptamers, with an impressive degree of accuracy

The rise of molecular simulations in fragment-based drug design (FBDD): an overview

Fragment-based drug discovery (FBDD) is an innovative approach, progressively more applied in the academic and industrial context, to enhance hit identification for previously considered undruggable biological targets. In particular, FBDD discovers low-molecular-weight (LMW) ligands (<300 Da) able to bind to therapeutically relevant macromolecules in an affinity range from the micromolar (\u3bcM) to millimolar (mM). X-ray crystallography (XRC) and nuclear magnetic resonance (NMR) spectroscopy are commonly the methods of choice to obtain 3D information about the bound ligand\u2013protein complex, but this can occasionally be problematic, mainly for early, low-affinity fragments. The recent development of computational fragment-based approaches provides a further strategy for improving the identification of fragment hits. In this review, we summarize the state of the art of molecular dynamics simulations approaches used in FBDD, and discuss limitations and future perspectives for these approaches

Comparing fragment binding posesprediction using HSP90 as a key study: When bound water makes the difference

Fragment-Based Drug Discovery (FBDD) approaches have gained popularitynot only in industry but also in academic research institutes.However, the computational prediction of the binding mode adopted by fragment-like molecules within a protein binding site is still a very challenging task. One of the most crucial aspects of fragment binding is related to the large amounts of bound waters in the targeted binding pocket. The binding affinity of fragmentsmay not be sufficientto displace the bound water molecules. In the present work, we confirmed the importance of the bound water molecules in the correct prediction of the fragment binding mode.Moreover, we investigate whether the use of methods based on explicit solvent molecular dynamics simulations can improve the accuracy of fragment posing. The protein chosen for this study is HSP-90