A community effort in SARS-CoV-2 drug discovery

: The COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the "Billion molecules against COVID-19 challenge", to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 molecules, which were subsequently ranked to find 'consensus compounds'. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for biological activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (only the Nsp12 domain), and (alpha) spike protein S. Overall, 27 compounds with weak inhibition/binding were experimentally identified by binding-, cleavage-, and/or viral suppression assays and are presented here. Open science approaches such as the one presented here contribute to the knowledge base of future drug discovery efforts in finding better SARS-CoV-2 treatments

A community effort in SARS-CoV-2 drug discovery.

peer reviewedThe COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the "Billion molecules against Covid-19 challenge", to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 molecules, which were subsequently ranked to find 'consensus compounds'. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for biological activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (only the Nsp12 domain), and (alpha) spike protein S. Overall, 27 compounds with weak inhibition/binding were experimentally identified by binding-, cleavage-, and/or viral suppression assays and are presented here. Open science approaches such as the one presented here contribute to the knowledge base of future drug discovery efforts in finding better SARS-CoV-2 treatments.R-AGR-3826 - COVID19-14715687-CovScreen (01/06/2020 - 31/01/2021) - GLAAB Enric

Multi-layer Combinatorial Fusion using Cognitive Diversity

CCBY Multiple scoring systems (including rank and score functions; MSS) have been widely used in multiple regression, intelligent biometric systems, multiple artificial neural nets, combining pattern classifiers, ensemble methods, machine learning and artificial intelligence (AI), data and information fusion, preference ranking, and deep learning. Combining MSS has achieved numerous successful results in a variety of domain applications. However, the reasons why this happens remains an active area of investigation. Combinatorial fusion analysis (CFA) combines MSS using the rank-score characteristic (RSC) function and cognitive diversity (CD). The RSC function was proposed [1] to characterise the predictive behaviour of a scoring system. It was subsequently used to define the notion of “cognitive diversity” which measures the dissimilarity, in the representation of information, between two scoring systems. In this paper, we first examine characterizations of and diversity between scoring systems. Then, we review combinatorial fusion analysis with a variety of domain applications, including biometric systems in cognitive neuroscience, and joint decision making with visual cognitive systems. Finally, we demonstrate that multi-layer combinatorial fusion (MCF) on the Kemeny rank space is a viable machine learning and AI framework for preference ranking and reinforcement learning. This work provides a scientific foundation and technological insights for the use of Combinatorial Fusion in ensemble methods, data and information fusion, preference ranking, and deep reinforcement learning with applications to a variety of domains in data science and informatics for secure and sustainable societies

BioNetFit: a fitting tool compatible with BioNetGen, NFsim and distributed computing environments

Rule-based models are analyzed with specialized simulators, such as those provided by the BioNetGen and NFsim open-source software packages. Here, we present BioNetFit, a general-purpose fitting tool that is compatible with BioNetGen and NFsim. BioNetFit is designed to take advantage of distributed computing resources. This feature facilitates fitting (i.e. optimization of parameter values for consistency with data) when simulations are computationally expensive

Halogen interactions in protein-ligand complexes: Implications of halogen bonding for rational drug design

Halogen bonding interactions between halogenated ligands and proteins were examined using the crystal structures deposited to date in the PDB. The data was analyzed as a function of halogen bonding to main chain Lewis bases, viz. oxygen of backbone carbonyl and backbone amide nitrogen. This analysis also examined halogen bonding to side-chain Lewis bases (O, N, and S) and to the electron-rich aromatic amino acids. All interactions were restricted to van der Waals radii with respective atoms. The data reveals that while fluorine and chlorine have strong tendencies favoring interactions with the backbone Lewis bases at glycine, the trend is not restricted to the achiral amino acid backbone for larger halogens. Halogen side-chain interactions are not restricted to amino acids containing O, N, and S as Lewis bases. Electron-rich aromatic amino acids host a high frequency of halogen bonds as does Leu. A closer examination of the latter hydrophobic side chain reveals that the propensity of interactions of halogen ligands at this oily residue is an outcome of strong classical halogen bonds with Lewis bases in the vicinity. Finally, an examination of Θ1 (C-X⋯O and C-X⋯N) and Θ2 (X⋯O-Z and X⋯N-Z) angles reveals that very few ligands adopt classical halogen bonding angles, suggesting that steric and other factors may influence these angles. The data is discussed in the context of ligand design for pharmaceutical applications. © 2013 American Chemical Society