DeLA-DrugSelf: Empowering multi-objective de novo design through SELFIES molecular representation.

In this paper, we introduce DeLA-DrugSelf, an upgraded version of DeLA-Drug [J. Chem. Inf. Model. 62 (2022) 1411-1424], which incorporates essential advancements for automated multi-objective de novo design. Unlike its predecessor, which relies on SMILES notation for molecular representation, DeLA-DrugSelf employs a novel and robust molecular representation string named SELFIES (SELF-referencing Embedded String). The generation process in DeLA-DrugSelf not only involves substitutions to the initial string representing the starting query molecule but also incorporates insertions and deletions. This enhancement makes DeLA-DrugSelf significantly more adept at executing data-driven scaffold decoration and lead optimization strategies. Remarkably, DeLA-DrugSelf explicitly addresses the SELFIES-related collapse issue, considering only collapse-free compounds during generation. These compounds undergo a rigorous quality metrics evaluation, highlighting substantial advancements in terms of drug-likeness, uniqueness, and novelty compared to the molecules generated by the previous version of the algorithm. To evaluate the potential of DeLA-DrugSelf as a mutational operator within a genetic algorithm framework for multi-objective optimization, we employed a fitness function based on Pareto dominance. Our objectives focused on target-oriented properties aimed at optimizing known cannabinoid receptor 2 (CB2R) ligands. The results obtained indicate that DeLA-DrugSelf, available as a user-friendly web platform (https://www.ba.ic.cnr.it/softwareic/delaself/), can effectively contribute to the data-driven optimization of starting bioactive molecules based on user-defined parameters.

Small Molecules for the Treatment of Long-COVID-Related Vascular Damage and Abnormal Blood Clotting: A Patent-Based Appraisal.

People affected by COVID-19 are exposed to, among others, abnormal clotting and endothelial dysfunction, which may result in deep vein thrombosis, cerebrovascular disorders, and ischemic and non-ischemic heart diseases, to mention a few. Treatments for COVID-19 include antiplatelet (e.g., aspirin, clopidogrel) and anticoagulant agents, but their impact on morbidity and mortality has not been proven. In addition, due to viremia-associated interconnected prothrombotic and proinflammatory events, anti-inflammatory drugs have also been investigated for their ability to mitigate against immune dysregulation due to the cytokine storm. By retrieving patent literature published in the last two years, small molecules patented for long-COVID-related blood clotting and hematological complications are herein examined, along with supporting evidence from preclinical and clinical studies. An overview of the main features and therapeutic potentials of small molecules is provided for the thromboxane receptor antagonist ramatroban, the pan-caspase inhibitor emricasan, and the sodium-hydrogen antiporter 1 (NHE-1) inhibitor rimeporide, as well as natural polyphenolic compounds.

Multicomponent Reaction-Assisted Drug Discovery: A Time- and Cost-Effective Green Approach Speeding Up Identification and Optimization of Anticancer Drugs.

Multicomponent reactions (MCRs) have emerged as a powerful strategy in synthetic organic chemistry due to their widespread applications in drug discovery and development. MCRs are flexible transformations in which three or more substrates react to form structurally complex products with high atomic efficiency. They are being increasingly appreciated as a highly exploratory and evolutionary tool by the medicinal chemistry community, opening the door to more sustainable, cost-effective and rapid synthesis of biologically active molecules. In recent years, MCR-based synthetic strategies have found extensive application in the field of drug discovery, and several anticancer drugs have been synthesized through MCRs. In this review, we present an overview of representative and recent literature examples documenting different approaches and applications of MCRs in the development of new anticancer drugs.

N-adamantyl-anthranil amide derivatives: New selective ligands for the cannabinoid receptor subtype 2 (CB2R).

Cannabinoid type 2 receptor (CB2R) is a G-protein-coupled receptor that, together with Cannabinoid type 1 receptor (CB1R), endogenous cannabinoids and enzymes responsible for their synthesis and degradation, forms the EndoCannabinoid System (ECS). In the last decade, several studies have shown that CB2R is overexpressed in activated central nervous system (CNS) microglia cells, in disorders based on an inflammatory state, such as neurodegenerative diseases, neuropathic pain, and cancer. For this reason, the anti-inflammatory and immune-modulatory potentials of CB2R ligands are emerging as a novel therapeutic approach. The design of selective ligands is however hampered by the high sequence homology of transmembrane domains of CB1R and CB2R. Based on a recent three-arm pharmacophore hypothesis and latest CB2R crystal structures, we designed, synthesized, and evaluated a series of new N-adamantyl-anthranil amide derivatives as CB2R selective ligands. Interestingly, this new class of compounds displayed a high affinity for human CB2R along with an excellent selectivity respect to CB1R. In this respect, compounds exhibiting the best pharmacodynamic profile in terms of CB2R affinity were also evaluated for the functional behavior and molecular docking simulations provided a sound rationale by highlighting the relevance of the arm 1 substitution to prompt CB2R action. Moreover, the modulation of the pro- and anti-inflammatory cytokines production was also investigated to exert the ability of the best compounds to modulate the inflammatory cascade.

Improved Patient Recovery With Minimally Invasive Aortic Valve Surgery: A Propensity-Matched Study.

OBJECTIVE: Despite conflicting evidence available, minimally invasive aortic valve replacement (MIAVR) is increasingly used as an alternative to full sternotomy. We sought to compare early outcomes of aortic valve replacement through a full sternotomy (conventional aortic valve replacement [CAVR]) and upper ministernotomy (MIAVR). METHODS: We analyzed 297 patients having undergone primary, elective, isolated MIAVR or CAVR between January 2014 and June 2018. Following propensity score matching, 120 patients remained in each group. RESULTS: MIAVR required longer bypass (93 ± 26 vs 81 ± 24 minutes, P < 0.01) and operative times (214 ± 39 vs 182 ± 37 minutes, P < 0.01). However, aortic cross-clamp times were comparable (57 ± 17 vs 54 ± 14 minutes for MIAVR and CAVR, respectively, P = 0.14). MIAVR had less 24-hour blood loss (253 ± 204 vs 323 ± 296 mL, P = 0.03), less red blood cells transfusions [1.4 packs (1.1 o 1.9) vs 2.1 packs (1.8 to 2.7), P = 0.01], and shorter assisted ventilation time (7.1 ± 3.3 vs 9.7 ± 3.8 hours, P < 0.01) when compared to CAVR. These results led to significantly shorter intensive care unit and hospital stays for MIAVR patients (2.5 ± 1.3 vs 3.4 ± 1.1 days, P < 0.01 and 6.9 ± 4.1 vs 8.2 ± 4.8 days, P = 0.03, respectively). Thirty-day mortality and clinical outcomes did not differ significantly among groups. CONCLUSIONS: MIAVR through upper ministernotomy was shown to be as safe and reliable as CAVR. Patient recovery time was improved by shortening mechanical ventilation and reducing blood loss and transfusions. These results may be significant for high-risk patients undergoing aortic valve surgery.

Delayed massive subcutaneous emphysema following Robicsek closure.

A surgical procedure may lead to unusual and unexpected clinical scenario. Good medical practice should always keep it in mind. So, a broken sternal steel wire was the rare cause of massive emphysema.