Leishmania species are the causative agents for Leishmaniasis which is one of the neglected tropical diseases causing 70,000 deaths worldwide each year. Squalene synthase enzyme plays a vital role in sterol metabolism which is essential for Leishmania parasite viability. Therefore squalene synthase of Leishmania donovani is a therapeutic target to inhibit growth of parasite. The 3D model of Leishmania donovani Squalene Synthase (LdSQS) was generated by homology modeling and validated through PROCHECK, ERRAT, VERIFY3D and PROSA tools. Virtual screening of the protein was performed by AutoDock with reported inhibitor, E5700 and two natural alkaloids. Molecular interactions were explored to understand the nature of intermolecular bonds between active ligand and the protein binding site residues using UCSF Chimera and PLIP server. The reported inhibitor showed the best binding affinity (-9.75 kcal/mol) closely followed by Ancistrotanzanine B (-9.55 kcal/mol) and Holamine (-8.79 kcal/mol). Ancistrotanzanine B showed low binding energy and permissible ADMET properties. Based on the present study, homology model of LdSQS and Ancistrotanzanine B can be used to design inhibitors with antileishmanial activity.

Aims The parasite, Leishmania donovani is responsible for lethal visceral leishmaniasis (VL) in humans. There is a need to investigate novel medicines as antileishmanial drugs, as medication currently introduced for leishmaniasis may cause resistance, serious side-effects, chemical instability and high cost. Therefore, this computational study was designed to explore potential phytochemical inhibitors against Leishmania donovani squalene synthase (LdSQS) enzyme, a drug target. Main methods Multiple sequence alignment was carried to detect conserved regions across squalene synthases from different Leishmania spp. Their evolutionary relationships were studied by generating phylogenetic tree. Homology modeling method was used to build a three dimensional model of the protein. The validated model was explored by docking simulation with the phytochemicals of interest to identify the most potent inhibitors. Two reported inhibitors were used as references in the virtual screening. The top hit compounds (binding energy less than -9 kcal/mol) were further subjected to intermolecular interaction analysis, pharmacophore modeling, pharmacokinetic and toxicity prediction. Key findings Seven phytochemicals displayed binding energies less than -9 kcal/mol hence demonstrating ability to be strongly bound to the active site of LdSQS to inhibit the enzymatic activity. Ancistrotanzanine B demonstrated the lowest binding affinity of -9.83 kcal/mol superior to reported inhibitors in literature. Conserved two aspartate rich regions and two signatory motifs were found in the L. donovani squalene synthase by multiple sequence alignment. In addition, study of pharmacophore modeling confirmed that top hit phytochemicals and the reported inhibitor (E5700) share common chemical features for their biochemical interaction with LdSQS. Among seven phytochemicals, 3-O-methyldiplacol showed admissible physicochemical, pharmacokinetic and toxicity predictions compared to the reported inhibitors. All seven phytochemicals satisfied in silico prediction criteria for oral bioavailability. Significance Based on the current study, these hits can be further structurally optimized and validated under laboratory conditions to develop antileishmanial drugs.

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Despite COVID-19 vaccination, immune escape of new SARS-CoV-2 variants has created an urgent priority to identify additional antiviral drugs. Targeting main protease (M pro ) expressed by SARS-CoV-2 is a therapeutic strategy for drug development due to its prominent role in viral replication cycle. Leaves of Murraya koenigii are used in various traditional medicinal applications and this plant is known as a rich source of carbazole alkaloids. Thus, this computational study was designed to investigate the inhibitory potential of carbazole alkaloids from Murraya koenigii against M pro . Molecular docking was initially used to determine the binding affinity and molecular interactions of carbazole alkaloids and the reference inhibitor (3WL) in the active site of SARS-CoV-2 M pro (PDB ID: 6M2N).The top scoring compounds were further assessed for protein structure flexibility, physicochemical properties and drug-likeness, pharmacokinetic and toxicity (ADME/T) properties, antiviral activity, and pharmacophore modeling. Five carbazole alkaloids (koenigicine, mukonicine, o -methylmurrayamine A, koenine, and girinimbine) displayed a unique binding mechanism that shielded the catalytic dyad of M pro with stronger binding affinities and molecular interactions than 3WL. Furthermore, the compounds with high affinity displayed favorable physicochemical and ADME/T properties that satisfied the criteria for oral bioavailability and druggability. The pharmacophore modeling study shows shared pharmacophoric features of those compounds for their biological interaction with M pro . During the molecular dynamics simulation, the top docking complexes demonstrated precise stability except koenigicine. Therefore, mukonicine, o -methylmurrayamine A, koenine, and girinimbine may have the potential to restrict SARS-CoV-2 replication by inactivating the M pro catalytic activity. Supplementary Information The online version contains supplementary material available at 10.1007/s12010-022-04138-6.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen for the novel COVID-19 disease. SARS-CoV-2 papain-like protease (PLpro) is responsible for viral replication and host innate immunity suppression. Thus, this study aimed to explore potential phytochemical inhibitors against this dual therapeutic target using virtual screening methods. Thirty-one phytochemicals with reported anti-SARS-CoV-1 PLpro activity were used to construct the phytochemical library along with two positive controls. Molecular docking using AutoDock 4.2 was employed to calculate binding affinity and inhibition constant of each compound within the S3/S4 binding pocket of SARS-CoV-2 PLpro. Based on the docking results, twelve compounds were subjected to non-covalent interaction analysis utilizing the Discovery Studio Visualizer software. Further, their physicochemical, pharmacokinetics and toxicity descriptors were evaluated using molinspiration and pkCSM web servers, respectively. Hirsutenone from Alnus japonica and broussoflavan A from Broussonetia papyrifera, displayed the strongest binding affinity (-8.23 kcal/mol and -8.13 kcal/mol), lowest inhibition constant (920.39 nM and 1.1 μM) and highest ligand efficiency (0.34 and 0.26) among all phytochemicals towards the binding pocket of SARS-CoV-2 PLpro, demonstrating superiority to PLpro inhibitors, 3k and GRL0617 which were used as positive controls. Additionally, hirsutenone, broussoflavan A and broussochalcone A (from Broussonetia papyrifera) possessed favorable physicochemical properties for oral drug development, satisfying Lipinski’s and Veber’s rules. Furthermore, in silico pharmacokinetics and toxicity predictions revealed that the three aforementioned phytochemicals are water soluble, non-mutagenic, non-hepatotoxic and biologically safe. Hence these lead compounds might be exploited to accelerate the drug discovery process against the ongoing COVID-19 infection.