The emergence of drug resistant strains of Mycobacterium Tuberculosis (Mtb) accentuates the urgent need for the development of novel antitubercular drugs. The major causes of drug resistance are genetic mutations, the influx-efflux transporter system, and the complex cell wall system of Mtb, which can function as permeability barriers. The driving force for permeability of small molecules through a biological system depends on various physicochemical factors. To understand the permeability of small molecules and subsequent cell inhibition, we have developed predictive QSAR models based on reported enzyme-based (IC) and cell-based (MIC) Mtb inhibitory data. The compounds that are highly active in enzyme-based assays and have significant variation in cell-based assays are assumed to possess the required permeability through the Mtb cell wall. The obtained models suggest the importance of molecular connectivity, lipophilicity (log P, size, shape), electrotopology (relative atomic mass, polarizability, electronegativity, ionization potential, atomic charges, van der Waals volume, hybridization, hydrogen bond acceptors/donors, number of fused rings) and functional groups (hydroxyl groups, primary and secondary amines) of a molecule in determining both its inhibitory potency and Mtb cell permeability. The models were validated with known Mtb inhibitors (9804) collected from the ChEMBL database, Mtb drugs (27) and clinical candidates (5). Further, these validated models were used to screen and prioritize a large database of compounds, including Zinc (152 128), Asinex (435 215), DrugBank (6531) and antimicrobial compounds (1324). The results obtained from 2D-QSAR analysis could improve our understanding towards Mtb cell permeability, which may aid in the rational design of novel potent molecules for tuberculosis (TB).
Molecular Property Diagnostic Suite (MPDS TB ) is a web tool (http://mpds.osdd.net) designed to assist the in silico drug discovery attempts towards Mycobacterium tuberculosis (Mtb). MPDS TB tool has nine modules which are classified into data library (1-3), data processing (4-5) and data analysis (6-9). Module 1 is a repository of literature and related information available on the Mtb. Module 2 deals with the protein target analysis of the chosen disease area. Module 3 is the compound library consisting of 110.31 million unique molecules generated from public domain databases and custom designed search tools. Module 4 contains tools for chemical file format conversions and 2D to 3D coordinate conversions. Module 5 helps in calculating the molecular descriptors. Module 6 specifically handles QSAR model development tools using descriptors generated in the Module 5. Module 7 integrates the AutoDock Vina algorithm for docking, while module 8 provides screening filters. Module 9 provides the necessary visualization tools for both small and large molecules. The workflow-based open source web portal, MPDS TB 1.0.1 can be a potential enabler for scientists engaged in drug discovery in general and in anti-TB research in particular.
A fragment-based drug discovery (FBDD) approach has traditionally been of utmost significance in drug design studies. It allows the exploration of large chemical space to find novel scaffolds and chemotypes which can be improved into selective inhibitors with good affinity. In the current work, several public domain chemical libraries (ChEMBL, DrugCentral, PDB ligands, COCONUT, and SAVI) comprising bioactive and virtual molecules were retrieved to develop a fragment library. A systematic fragmentation method that breaks a given molecule into rings, linkers, and substituents was used to cleave the molecules and the fragments were analyzed. Further, only the ring framework was taken into the consideration to develop a fragment library that consists of a total number of 107,614 unique fragments. This set represents a rich diverse structure framework that covers a wide variety of yet-to-be-explored fragments for a wide range of small molecule-based applications. This fragment library is an integral part of the molecular property diagnostic suite (MPDS) suite that can be used with other modeling and informatics methods for FBDD approaches. The fragment library module of MPDS can be accessed at http://mpds.neist.res.in:8085 . Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11030-022-10506-5.
Many-body expansion (MBE) has been carried out to investigate two-to five-body energy terms and their contributions to the interaction energy (IE) of (H 2 O) 15 cluster. We have observed that the erroneous contribution of many-body terms on IE originated from cheaper convergence thresholds set as default in popular quantum mechanics packages. The propagation of errors from smaller to higher-body terms, due to the combinatorial nature of MBE, is also observed.
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