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Malaria remains a deadliest disease brought about by Plasmodium species, among one of these species, disease due to Plasmodium falciparum (Pf) is life-threatening. The structures of PfLDH and human LDH are very similar in terms of L-LDH activity, and their biological functions are also equivalent. Therefore, any treatment aiming blocking the functions of PfLDH can affect human LDH. Thus, the main objective of this study is to identify the molecule that exhibits selectivity towards PfLDH without a profound effect on human LDH. In this research, a set of 68 quinolines based molecules were used for molecular docking. From molecular docking, we selected molecules 3j, 4b, 4h, 4m based on their binding affinity, ligand efficiency, lipophilic ligand efficiency, and torsion with selectivity towards PfLDH. The stability of the docked molecules was compared to Chloroquine (reference inhibitor) by applying molecular dynamics simulations and molecular mechanics poisson boltzmann surface area calculations. All the selected molecules showed selectivity for PfLDH with stable dynamic behavior and high binding free energy in comparison to Chloroquine. After examining the molecular mechanics poisson boltzmann surface area ratio results, molecule 3j was reported as a potential and specific inhibitor for PfLDH with a novel mechanism of binding to PfLDH while the remaining molecules 4b, 4h, 4m could further be modified to be used as potent inhibitors against malarial infection.

Cyclin-dependent kinases (CDKs) are known for their vital role in regulating cell cycle progression through protein-kinase interactions. CDKs also help in regulating transcription and development of the central nervous system. Inhibition of CDKs is a very fundamental approach for drug discovery in areas of different types of cancers, Alzheimer's, and HIV infections. The present research focuses on finding a novel, potent, and specific natural inhibitors of CDK isoforms (CDK2, CDK5, CDK7, CDK9). Molecular docking, molecular dynamics (MD) simulations, and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) were carried out to get an in-depth understanding of protein-ligand interactions. Based on our molecular docking results, Ligands-3, 5, 14, and 16 were screened among 17 different Pyrrolone-fused benzosuberene compounds as potent and specific inhibitors without any cross-reactivity against different CDK isoforms. Analysis of MD simulations and MM-PBSA studies, revealed the binding energy profiles of all the selected complexes. Our selected ligands performed better than the standard inhibitor (Roscovitine). Ligands-3 and 14 show specificity for CDK7 and Ligands-5 and 16 were specific against CDK9. These ligands are expected to possess lower risk of side effects due to their natural origin. Moreover, the backbone structure of these ligands could also be exploited to develop specific inhibitors against other CDK isoforms.Communicated by Ramaswamy H. Sarma.

Amyotrophic lateral sclerosis 6 (ALS6) is an autosomal recessive disorder caused by heterozygous mutation in the Fused in Sarcoma (FUS) gene. ALS6 is a neurodegenerative disorder, which affects the upper and lower motor neurons in the brain and spinal cord, resulting in fatal paralysis. ALS6 is caused by the genetic mutation in the proline/tyrosine-nuclear localization signals of the Fused in sarcoma Protein (FUS). FUS gene also known as TLS (Translocated in liposarcoma), which encodes a protein called RNA-binding protein-Fus (FUS), has a molecular weight of 75 kDa. In this analysis, we applied computational approach to filter the most deleterious and neurodegenerative disease of ALS6-associated mutation on FUS protein. We found H517Q as most deleterious and disease associated using PolyPhen 2.0, I-Mutant 3.0, SIFT, SNPsGO, PhD-SNP, Pmut, and Mutpred tools. Molecular dynamics simulation (MDS) approach was conducted to investigate conformational changes in the mutant protein structure with respect to its native conformation. MDS results showed the flexibility loss in mutant (H517Q) FUS protein. Due to mutation, FUS protein became more rigid in nature and might alter the structural and functional behavior of protein and play a major role in inducing ALS6. The results obtained from this investigation would help in the field of pharmacogenomics to develop a potent drug target against FUS-associated neurodegenerative diseases.

CK1δ (Casein kinase I isoform delta) is a member of CK1 kinase family protein that mediates neurite outgrowth and the function as brain-specific microtubule-associated protein. ATP binding kinase domain of CK1δ is essential for regulating several key cell cycle signal transduction pathways. Mutation in CK1δ protein is reported to cause cancers and affects normal brain development. S97C mutation in kinase domain of CK1δ protein has been involved to induce breast cancer and ductal carcinoma. We performed molecular docking studies to examine the effect of this mutation on its ATP-binding affinity. Further, we conducted molecular dynamics simulations to understand the structural consequences of S97C mutation over the kinase domain of CK1δ protein. Docking results indicated the loss of ATP-binding affinity of mutant structure, which were further rationalized by molecular dynamics simulations, where a notable loss in 3-D conformation of CK1δ kinase domain was observed in mutant as compared to native. Our results explained the underlying molecular mechanism behind the observed cancer associated phenotype caused by S97C mutation in CK1δ protein.

Drug resistant mutations have severely restricted the success of HIV therapy. These mutations frequently involve the aspartic protease encoded by the virus. Knowledge of the molecular mechanisms underlying the conformational changes of HIV-1 protease mutants may be useful in developing more effective and longer lasting treatment regimes. The flap regions of the protease are the target of a particular type of mutations occurring far from the active site, which are able to produce significant resistance against the anti-HIV drug TMC-114. We provide insight into the molecular basis of TMC-114 resistance major flap mutations (I50V and I54M) in HIV-1 protease. It reports the shape complementarity and receptor-ligand interaction analysis supported by unrestrained all-atom molecular dynamics simulations of wild and major flap mutants of HIV-1 protease that sample large conformational changes of the flaps and active site binding residues. Both resistant flap mutants showed less atomic interaction toward TMC-114 and more structural deviation compared to wild HIV-protease. It is due to increasing flexibility at TMC-114 binding cavity and deviation of binding residues in 3-D space. Distortion in binding cavity and deviation in binding residues are the result of alteration in hydrogen bonding. Flap region also exhibited similar behaviour due to changes in number of hydrogen bonds during simulations.