Leishmaniasis, a category 1 neglected protozoan disease caused by a kinetoplastid pathogen called Leishmania, is transmitted through dipteran insect vectors (phlebotomine, sand flies) in three main clinical forms: fatal visceral leishmaniasis, self-healing cutaneous leishmaniasis, and mucocutaneous leishmaniasis. Generic pentavalent antimonials have long been the drug of choice against leishmaniasis; however, their success is plagued with limitations such as drug resistance and severe side effects, which makes them redundant as frontline therapy for endemic visceral leishmaniasis. Alternative therapeutic regimens based on amphotericin B, miltefosine, and paromomycin have also been approved. Due to the unavailability of human vaccines, first-line chemotherapies such as pentavalent antimonials, pentamidine, and amphotericin B are the only options to treat infected individuals. The higher toxicity, adverse effects, and perceived cost of these pharmaceutics, coupled with the emergence of parasite resistance and disease relapse, makes it urgent to identify new, rationalized drug targets for the improvement in disease management and palliative care for patients. This has become an emergent need and more relevant due to the lack of information on validated molecular resistance markers for the monitoring and surveillance of changes in drug sensitivity and resistance. The present study reviewed the recent advances in chemotherapeutic regimens by targeting novel drugs using several strategies including bioinformatics to gain new insight into leishmaniasis. Leishmania has unique enzymes and biochemical pathways that are distinct from those of its mammalian hosts. In light of the limited number of available antileishmanial drugs, the identification of novel drug targets and studying the molecular and cellular aspects of these drugs in the parasite and its host is critical to design specific inhibitors targeting and controlling the parasite. The biochemical characterization of unique Leishmania-specific enzymes can be used as tools to read through possible drug targets. In this review, we discuss relevant metabolic pathways and novel drugs that are unique, essential, and linked to the survival of the parasite based on bioinformatics and cellular and biochemical analyses.

Glutamine Synthetase (GS) is functionally important in many pathogens, so its viability as a drug target has been widely investigated. We identified Leishmania major glutamine synthetase (Lm-GS) as an appealing target for developing potential leishmaniasis inhibitors. Comparative modeling, virtual screening, MD simulations along with MM-PBSA analyses were performed and two FDA approved compounds namely Chlortalidone (id ZINC00020253) and Ciprofloxacin (id ZINC00020220) were identified as potential inhibitor among the screened library. These compounds may be used as a lead molecule, although additional in vitro and in vivo testing is required to establish its anti-leishmanial effect. Hence, the goal of this study was to locate and identify certain medications that were previously FDA-approved for definite disorders and that might show anti-leishmanial effect. Due to GS's presence in additional Leishmania species, a novel medication docked with Lm-GS may have broad anti-leishmania efficacy. Communicated by Ramaswamy H. Sarma

To identify and validate novel small-molecule inhibitors targeting KRAS G12C, G12D, and G12V mutants through a structure-based drug design and experimental approach. We employed molecular docking, molecular dynamics (MD) simulations, MM-PBSA binding free energy calculations, and principal component analysis (PCA) to screen and evaluate potential inhibitors targeting the Switch-II pocket of KRAS mutants. Top-ranking compounds were experimentally validated using Bio-Layer Interferometry (BLI) for binding affinity and MTT assays to assess anticancer activity in breast and lung cancer cell lines. Compound C797-1505 showed strong binding to KRAS G12V (Dissociation constant (KD) = 141 µM), outperforming the reference Sotorasib (KD = 345 µM). C190-0346 displayed weak affinity toward KRAS G12C. MTT assays revealed that C797-1505 reduced breast cancer cell viability (Half-maximal Inhibitory Concentration (IC50) = 43.51 µM), while both compounds demonstrated significant cytotoxicity against lung cancer cells (IC50 = 18.78 µM and 22.93 µM, respectively). Our integrated computational and experimental strategies successfully identified selective KRAS mutant inhibitors with promising anticancer activity, particularly against G12V and G12C driven tumors. These findings support further development and preclinical evaluation of these compounds as targeted therapeutics.