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Helicobacter pylori (Hp) infections pose a global health challenge demanding innovative therapeutic strategies by which to eradicate them. Urease, a key Hp virulence factor hydrolyzes urea, facilitating bacterial survival in the acidic gastric environment. In this study, a multi-methodological approach combining pharmacophore- and structure-based virtual screening, molecular dynamics simulations, and MM-GBSA calculations was employed to identify novel inhibitors for Hp urease (HpU). A refined dataset of 8,271,505 small molecules from the ZINC15 database underwent pharmacokinetic and physicochemical filtering, resulting in 16% of compounds for pharmacophore-based virtual screening. Molecular docking simulations were performed in successive stages, utilizing HTVS, SP, and XP algorithms. Subsequent energetic re-scoring with MM-GBSA identified promising candidates interacting with distinct urease variants. Lys219, a residue critical for urea catalysis at the urease binding site, can manifest in two forms, neutral (LYN) or carbamylated (KCX). Notably, the evaluated molecules demonstrated different interaction and energetic patterns in both protein variants. Further evaluation through ADMET predictions highlighted compounds with favorable pharmacological profiles, leading to the identification of 15 candidates. Molecular dynamics simulations revealed comparable structural stability to the control DJM, with candidates 5, 8 and 12 (CA5, CA8, and CA12, respectively) exhibiting the lowest binding free energies. These inhibitors suggest a chelating capacity that is crucial for urease inhibition. The analysis underscores the potential of CA5, CA8, and CA12 as novel HpU inhibitors. Finally, we compare our candidates with the chemical space of urease inhibitors finding physicochemical similarities with potent agents such as thiourea.

This article develops recurrence relations for integrals that relate the density of multivariate extended skew-normal (ESN) distribution, including the well-known skew-normal (SN) distribution introduced by Azzalini and Dalla-Valle and the popular multivariate normal distribution. These recursions offer a fast computation of arbitrary order product moments of the multivariate truncated extended skew-normal and multivariate folded extended skew-normal distributions with the product moments as a byproduct. In addition to the recurrence approach, we realized that any arbitrary moment of the truncated multivariate extended skew-normal distribution can be computed using a corresponding moment of a truncated multivariate normal distribution, pointing the way to a faster algorithm since a less number of integrals is required for its computation which results much simpler to evaluate. Since there are several methods available to calculate the first two moments of a multivariate truncated normal distribution, we propose an optimized method that offers a better performance in terms of time and accuracy, in addition to consider extreme cases in which other methods fail. Finally, we present an application in finance where multivariate tail conditional expectation (MTCE) for SN distributed data is calculated using analytical expressions involving normal left-truncated moments. The R MomTrunc package provides these new efficient methods for practitioners. Supplementary files for this article are available online.